Cyclopentannulation : novel ring formation mediated by allylsilane functionality
by Kendal Troy Ryter
A thesis submitted in partial fulfillment Of the requirements for the degree of Doctor of Philosophy in
Chemistry
Montana State University
© Copyright by Kendal Troy Ryter (1998)
Abstract:
Synthetic methods designed for the production of natural products composed of or containing
five-membered rings selectively and efficiently are lacking in that few are general or applicable to
practical synthetic strategies. 2-(Trimethylsilylmethyl)prop-2-enyllithim has proven to be a very
effective reagent for the introduction of 2-(trimethylsilylmethyl)prop-2-en functionality to a wide
variety of electrophilic organic substrates. Copper and chlorotrimethylsilane mediated conjugate
addition of 2-(Trimethylsilylmethyl)prop-2-enyllithim to enones followed by efficient oxidative ring
closure utilizing a new reagent, dichloro(2,2,2-trifluoroethoxy)oxovanadium (V) provided
cyclopentenannulated products. The two step ring formation process proved to be general and selective
for various enones bearing functionality and substitution.. The new oxovanadium ester was also shown
much more selective in the synthesis of symmetrical and unsymmetrical 1,4-diketones.. A new
synthetic strategy directed toward the total synthesis of the natural products pentalene, pentalenic acid
and deoxypentalenic acid based on allyl bis(silane) functionality was investigated. CYCLOPENTANNULATION : NOVEL RING FORMATION
MEDIATED BY ALLYLSILANE FUNCTIONALITY
by
Kendal Troy Ryter
A thesis submitted in partial fulfillment
O f the requirements for the degree
of
Doctor o f Philosophy
in
Chemistry
MONTANA STATE UNIVERSITY-BOZEMAN
Bozeman, Montana
April 1998
11
APPROVAL
Of a thesis submitted by
Kendal Troy Ryter
The thesis has been read by each member o f the thesis committee and has been
found to be satisfactory regarding content, English usage, format, citations, bibliographic
style and consistency, and is ready for submission to the College o f Graduate studies.
Approved for the College o f Graduate Studies
r / s / r ?
Date
iii
STATEMENT OF PERMISSION TO USE
In presenting this thesis in partial fulfillment o f the requirements for a doctoral degree at
Montana State University-Bozeman, I agree that the Library shall make it available to
borrowers under rules o f the Library. I further agree that copying o f this thesis is
allowable only for scholarly purposes, consistent with “fair use” as prescribed in the U.S.
Copyright Law. Requests for extensive copying or reproduction o f this thesis should be
referred to University Microfilms International, 300 North Zeeb Road, Ann Arbor,
Michigan 48106, to whom I have granted “the exclusive right to reproduce and distribute
my dissertation in and from microform along with the non-exclusive right to reproduce
and distribute my abstract in any format in whole or in part.”
Signature
Date
^ /^ 7
^
iv
ACKNOWLEDGEMENTS
I
would like to thank my wife, Ellen, for everything she has done in supporting
me as I attempt to achieve my goals. I would also like to thank my parents, who have
shown their support throughout my scholastic career in many generous ways. Thanks
also to my in-laws, Roy and Bonnie Emerson for their support and generosity.
Completion o f this dissertation would not have been possible without the input and
efforts o f my colleagues and family.
I would like to acknowledge Brian Pagenkopf,
Donogh CTMahony and David Belanger for their commitment to producing quality work
and their ability to instill a level o f professionalism in others.
Possibly the most
important acknowledgement is that o f Professor Tom Livinghouse. I joined his research
group in reverence o f his ability and proficiency as a chemist. I only hope I take a small
part o f what he has taught with me.
TABLE OF CONTENTS
Page
INTRODUCTION...................................................................................................................... I
BACKGROUND........................................................................................................................ 4
Cyclopentannulation......................................................................................................4
Trimethylenemethane Synthons................................................................................... 9
Allyl Bis(silane) Reaction Terminators ...................................................................... 14
RESULTS AND DISCUSSION................................................................................
18
Investigations o f [2-(Trimethylsilylmethyl)prop-2-enyl]trimethylsilane..............18
Bifunctional Reagents: Development o f [2-(metallomethyl)prop-2enyl]trimethylsilanes.................................................................................................... 26
Conjugate Addition/ Oxidative Cyclization...............................................................34
Oxidative Coupling o f Silyl Enol Ethers...................................................................46
Attempted Synthesis o f Pentalenic A c id .................................................................... 51
SUM M ARY................................................................................................................................60
EXPERIMENTAL
...................................................................
REFERENCES............. .............................................................................................................83
APPENDIX................................................................................................................................. 87
Representative Spectra................................................................................................. 88
LIST OF TABLES
Table
-
'
Page
1. Reaction of 2-(Trimethylsilylmethyl)prop-2-enyllithium
with Representative Electrophiles.............................................................................32
2. 1,4-Addition of [2-(Metallomethyl)prop-2-enyl]trimethylsilanes to E n o n e s............... 40
3. Oxidative Cyclizatiqns o f 3 - [2-(trimethylsilylmethyl)prop-2-enyl Silyl
Enol Ethers by Dichloro(2,2,2-trifluqroethoxy)oxovanadium ( V ) ......................41
r
Vll
LIST OF FIGURES
Figure
Page ■
1. Characteristic carbocyclic skeleta o f polyquinane natural p ro d u cts..............................I
2. (±)Pentalenic A c id ...........................................................
3. Allyl bis(silanes).........................................................................
3
................................ 14
4. NOE results for structure 1 4 0 .............................................. ............................................ 42
5. Pentalene natural products.....................................
51
r
viii
ABSTRACT
. Synthetic methods designed for the production o f natural products
composed o f or containing five-membered rings selectively and efficiently are lacking in
that few are general or applicable to practical synthetic strategies.
2(Trimethylsilylmethyl)prop-2-enyllithim has proven to be a very effective reagent for the
introduction o f ' 2-(trimethylsilylmethyl)prop-2-en functionality to a wide variety o f
electrophilic organic substrates. Copper and chlorotrimethylsilane mediated conjugate
addition o f 2-(Trimethylsilylmethyl)prop-2-enyllithim to enones followed by efficient
oxidative
ring
closure
utilizing
a
new
reagent,
dichloro(2,2,2trifluoroethoxy)oxovanadium (V) provided cyclopentenannulated products. The two step
ring formation process proved to be general and selective for various enones bearing
functionality and substitution.. The new oxovanadium ester was also shown much more
selective in the synthesis o f symmetrical and unsymmetrical 1,4-diketones. A new
synthetic strategy directed toward the total synthesis o f the natural products pentalene,
pentalenic acid and deoxypentalenic acid based on allyl bis(silane) functionality was
investigated.
I
INTRODUCTION
Interest in synthetic methodology applicable to the preparation o f cyclopentanoid
natural products has been intense since the discovery o f monocyclic structures
comprising the prostaglandins1 and polyquinane natural products. Polyquinane skeleta
have been found in plant, marine and microbial sources and are composed o f rigid and
compact fused five-membered ring systems having four basic structures (Figure I).2
Figure I. Characteristic carbocyclic skeleta of polyquinane natural products.
Many polyquinanes, and/or their metabolites possess potent and diverse biological
activity.3 The combination o f structurally alluring molecules' and the potential for drug
discovery has fueled interest in polyquinane natural product synthesis and the subsequent
development o f synthetic strategies for cyclopentannulation.
The difficult task o f
selective formation o f functionalized cyclopentane rings is evident from the number o f
2
general procedures available for this transformation. Recent work in this area includes
improved versions o f the Nazarov cyclization,4,5,6 the Pauson-Khand reaction7 and
formal [ 4 + 1 ] and [3 + 2] cycloadditions.10' 11 In addition, the use o f organosilicon
reagents and synthons in the synthesis o f natural products has received considerable
attention.14b
Presented herein is an outline o f work completed detailing a new, highly efficient
and selective synthetic method whereupon allylsilane functionality may be introduced to
various electrophilic substrates through the use o f the bifunctional reagent [2(trimethylsilylmethyl)prop-2-enyl]lithium, I (Scheme I). This new reagent has also been
R = H , Me
Scheme I
shown to undergo transmetalation with copper salts allowing for silylative 1,4-addition to
enones to give silyl enol ethers in excellent yield and a high state o f purity. Oxidative
3
cyclization o f the silyl enol ether is accomplished through the use o f a novel
oxovanadium reagent. The overall process has proven to be a highly efficient and useful
method o f effecting methylenecyclopentannulation.
The knowledge gained
in the process o f these investigations and the
accomplishments o f co-workers in the area o f allyl bis(silane) chemistry19 is currently
being applied to the synthesis o f (±)-Pentalenic acid, 5.
CO2H
Figure 2. (+)-Pentalenic acid.
4
BACKGROUND
Cyclopentannulation
Cyclopentanoid
and
polyquinane
natural
products
have
stimulated
the
implementation o f new methods for the synthesis o f five-membered rings. The design
and development o f flexible routes using simple reagents under mild conditions is o f
central importance. Described herein are procedures that have been shown to be selective
and versatile for the formation o f cyclopentanoid structures.
The classical Nazarov cyclization4 has been extensively modified to incorporate
synthetic handles or functional groups that facilitate the reaction and control selectivity.
An improved version o f the Nazarov cyclization developed by Denmark and Jones relies
on the ability o f silicon to control the regio- and stereochemical outcome o f carbonium
ion processes (Scheme 2).5 The three step annulation has proven to be quite general for a
number o f substrates giving enones, 8, in moderate to synthetically useful yields. The
iron (HI) chloride mediated ring closure is dominated by the ability o f the vinyl silane
functionality to direct the introduction o f the new double bond at the least substituted
position.
5
O
OH
7
8
Scheme 2
A more recent advancement in the Nazarov cyclization strategy has been
developed by Ichikawa and co-workers in which the P-silane functionality has been
replaced with fluorine (Scheme 3 ) 6 Treatment o f dienones, such as 9a and 9b, with
trimethylsilyltriflate in a mixture o f hexafluoroisopropanol (HFIP) and methylene
chloride provides cyclized products in excellent yield. The P-cation destabilizing effect
o f fluorine atoms and the stability o f the fluoride anion as a leaving group allow for the
efficient formation o f cyclopentenones, 10a, b, with a high degree o f selectivity.
M-Bu
TM SO T f(IO eq)
w-Bu
CF2
HFIP : CH2Cl2, rt
IOa 92%
IOb 97%
9a n 1
9b n : 2
Scheme 3
6
Products o f the reaction possess one more double bond than previously reported Nazarov
cyclization products.
Further synthetic elaboration o f the (3-fluoro enones, 10, can be
accomplished easily by addition-elimination reactions o f carbon or hetero-atom
nucleophiles with the fluorine substituent.
A new and highly convergent cyclopentenone synthesis has recently been
developed in these laboratories, in an improved and truly catalytic version o f the PausonKhand reaction (Scheme 4).7 The formal [2 + 2 + 1 ] cycloaddition o f an alkene, alkyne
and carbon monoxide has been a popular means o f effecting selective organic
transformations. The rate-limiting factor o f the Pauson-Khand reaction has been thought
to be the dissociation o f carbon monoxide from the metal. The findings o f Livinghouse
and Pagenkopf suggest that decarbonylation o f the cobalt organometallic is promoted
with high-intensity visible light. Prior to this result nearly all Pauson-Khand reactions
required stoiciometric amounts o f Coz(CO); in order to effect efficient transformations
under mild conditions. This was a severe limitation for practical large-scale synthesis.
Co2(CO)8 (5 mol%)
CO (I atm), hv
DME, 50-55 0C
11
95%
12
Scheme 4
Transition metal-catalyzed carbonylation reactions have resulted in useful
methods for the formation o f five-membered rings. The rhodium(I)-catalyzed [ 4 + 1 ]
7
cycloaddition o f vinyl allenes 13 with carbon monoxide has recently been demonstrated
as an effective means o f forming functionalized cyclopentenones 16.8 The inclusion o f
chiral diphosphine ligands on rhodium(I) catalyst also gives rise to very good
enantioselectivity through the facially selective complexation o f the ligated metal
(Scheme 5).9
+ CO
- Rh(I)L1
80 - 96% Yield
60 - 95% ee
Scheme 5
O f continuing interest in cyclopentane ring formation is the development o f a
general procedure for the conversion o f conjugated dienes, 17, to cyclopentenes by means
o f a formal [ 4 + 1 ] cycloaddition. Similarities o f this transformation to the Diels-Alder [4
+ 2] reactions for cyclohexane ring formation would suggest that a high degree o f regioand stereoselectivity might be achieved.
8
Rieke and co-workers have recently reported an efficient [ 4 + 1 ] cycloaddition
process.
Treatment o f 1,3-conjugated dienes, 17, with activated magnesium gives a
highly reactive intermediate, 18, which will attack various electrophiles (Scheme 6).10
One o f many examples is the reaction o f the bound magnesium intermediate with an
ester, which presumably forms the intermediate 19. Heating the resultant cyclopropane,
20, to reflux induces ring expansion to provide various substituted cyclopentenols, 21.
The overall process represents an efficient, one pot, formal [ 4 + 1 ] annulation process.
20
21
Scheme 6
Danheiser
and
co-workers
have
also
identified
a
procedure
for
(trimethylsilyl)cyclopentene annulation by means o f an allenylsilane-enone [3 + 2]
cycloaddition (Scheme 7).11 Trimethylsilyl allenes, 22, serve as effective bifunctional
three-carbon sources for electrophilic addition to Lewis acid activated enones.
The
9
'
resultant vinyl cation, 23, is then trapped by the titanium enolate yielding the new fivemembered ring, 24.
Scheme 7
Trimethylenemethane Synthons
Another means o f effecting cyclopentannulations based on trimethylenemethane
synthons is the palladium or nickel catalyzed reaction o f methylenecyclopropanes, 26,
with enones (Scheme 8).12
10
O
6
/Zi-CsH11
(|
+
Pd(O), 'Pr3P
.
^
120 0C
25
26
c „
Zi-C5H n
27
68%
Scheme 8
The harsh reaction conditions and the electronic requirements o f the cyclopropene limit
the synthetic utility o f the reaction. In most cases substitution on the cyclopropene is
limited to simple phenyl or alkyl moieties and reactions o f unsymmetrical cyclopropenes
or electrophiles result in the formation o f all possible regioisomers.
In 1979, Bates and co-workers illustrated the possibilities o f utilizing bifunctional
reagents in the preparation o f symmetrically substituted trimethylenemethane synthons.
Symmetrical reagents, 30, were easily prepared from the reaction o f the dianion o f
isobutene, 28, with an excess o f electrophile Ei (Scheme 9).13 Attempts at creating
unsymmetrical
trimethylenemethane
synthons
by
treating
the
dianion
with
an
electrophile, Ei, followed by the addition o f a second electrophile proved futile giving the
diadduct 32 in < 30% yield depending on the nature o f the electrophile, Ez.
11
31
32
Scheme 9
The search for a method o f generating a bifunctional conjunctive reagent has
resulted in investigations o f the palladium catalyzed reaction o f 2-(trimethylsilylmethyl)2-prop-l-enyl acetate, 34, with various enones (Scheme IO).14 The generality o f the
process has been proven for many electrophilic olefins, however, 2-cyclohexenone reacts
sluggishly under these conditions. In addition, a - or ^-substitution on the enone is not
tolerated.
Pd(Ph3P)4
+
Me3Si
OAc
THF (reflux)
33
34
17-85%
Scheme 10
Majetich and co-workers have recently reported the synthesis and reactions o f two
mixed bifunctionalized reagents, [2-((methyldiphenylsilyl)methyl)prop-2-enyl]trimethylsilane, 36, and [2-((trimethylsilyl)methylprop-2-enyl]tri-AZ-butylstannane, 40.15 Under
Lewis
acid
conditions
allyltrimethylsilane
allylmethyldiphenylsilane (Scheme 11).
reacts
more
readily
than
The inclusion o f both functionalities in one
synthon should allow for selectivity in the order with which they react.
Activation of
benzaldehyde with diethyl aluminum chloride followed by addition o f the unsymmetrical
allyl
bis(silane)
36
methyldiphenylsilane.
gave
the
desired
alcohol
37,
leaving
the
less
reactive
Protection o f the alcohol 37, followed by the annulation o f a
second equivalent o f benzaldehyde from treatment o f allylsilane 38 with a fluonde source
generated the substitutionally differentiated alcohol 39.
37
36
SiPh2Me
PhCHO, F
87%
Ph
OH
OAc
39
38
Scheme 11
13
Differences in the reactivity o f allylstannanes and allylsilanes can also be
exploited in reactions involving the bifunctional reagent 40 (Scheme 12).
By simply
heating the reagent with an aldehyde, only the allylstannane moiety is induced to react to
give allylsilane 41. In contrast, the selective reaction o f the allylsilane may be employed
by fluoride ion assisted addition to give the allylstannane 42.
40
41
42
Scheme 12
The successful formation o f 2-(2-hydroxyethyl)allylsilanes 44 has been o f interest
for quite some time. The indium mediated allylsilylation o f carbonyl compounds with 3iodo-2-(trimethylsilylmethyl)-propene 43 gives the addition products 44 (Scheme 13).16
The process is quite useful for reactions with various benzaldehydes, but gives only
moderate conversions result when alkyl aldehydes are employed as substrates.
14
RCOR' +
SiMe3
Scheme 12
Allyl Bis(silane) Reaction Terminators.
The use o f allylsilanes as reaction terminators in the formation o f carbon-carbon
bonds has been well documented.17 Since the original work o f Sakurai et al.18 illustrating
the utility o f allylsilanes in Michael addition reactions with enones in the presence o f
Lewis acids, a vast and rich field o f silicon chemistry has evolved.
Until recently
however, little attention has been given to the synthetic characteristics o f allyl bis(silane)
functionalities, 45 (Figure 3). This has been due, in large part, to the lack o f synthetic
processes that could elaborate compounds and install the desired allyl bis(silane)
functionality.
Figure 3. Allyl bis(silanes)
15
Kercher and Livinghouse have shown that 1,1-dibromoalkenes 46 react efficiently
with bis(trimethylsilylmethyl)zinc under catalytic palladium conditions to give bis
allyl(silanes) 47 in excellent isolated yield, typically greater than 80% for the two-step
transformation, from the aldehyde (Scheme 14).19
R
CHO
CBr4, PPh3
(TMSCH2)2Zn
R
SiMe3
CBr2
CH2Cl2
SiMe3
(PPh3)2PdCl2
THFj O 0C
46
47
Scheme 14
The construction o f 2-propylidene-l,3-bis(silane) imine 48 is an efficient process giving
rise to a series o f binary nucleophiles which react intramolecularly yielding as cyclized
products pyrrolizidines 49 and isotropanes 51 (Scheme 1 5 )19
i) C H 2O, H2O-THF
SiMe3
ii) TFA
H2C
51
Scheme 15
16
The azatricyclic core o f stemofoline, 55, could conceivably be constructed through this
type o f process. Intramolecular reaction o f allyl bis(silane) 52 with the imine yielded a
pyrrolizidone which was converted to the thiolactam 53 in 78% yield for the two steps
(Figure 16).
Treatment o f 53 with Meerwein’s salt provided the bridged tricyclic
pyrrolizidine 54.20
Me
Me3S i ^ y b r y
1) TiCl 4, CH2Cl2
-78 0C to rt
2) Lawesson's Reagent
Me3Si
78%
SI
Et3O+BF4'
O 0C t o r t
90%
O
Stemofoline
Scheme 16
In
1991,
Miginiac
and
co-workers
reported
the
synthesis
of
2-
(trimethylsilylmethyl)allyltrimethylsilane, 57 (Scheme 17).21 We envisioned that the
bifunctionality o f this new reagent could be utilized in tandem Lewis acid mediated
conjugate addition-cyclization reactions with sulfinyl enones, 56 (R3 = SOAr).
17
Alternatively, a bifunctional reagent o f the type 58 could serve as an intermolecular
linking agent for the introduction o f allylsilane functionality to a variety o f electrophilic
substrates.
-
^ R
R2
2
*
56
55
R 1= H ,Me, SAr
R2 = H, Me
R3 = H, Me, SOAr
Me3S i \ J l ^ R 4
57 R4 = SiMe3
58 R4 = M
Scheme 17
Transmetallation would lead to the formation o f synthetically complementary [2(metallomethyl)prop-2-enyl]trimethylsilanes, 58 (R4 = CuLn, ZnLn, etc ).
Silylative
conjugate addition o f the metallo- derivative to an appropriate acceptor, for example
enone 56 (R3 = H, Me), followed by oxidative cyclization o f the resultant silyl enol ether
would
constitute
an
efficient
methylenecyclopentannulations.
and
versatile
means
of
effecting
18
RESULTS AND DISCUSSION
Investigation o f [2-(Trimethylsilylmethyl)prop-2-enyl]trimethylsilane, 57
Research described herein is devoted to the development o f new methods for the
construction o f functionalized cyclopentane rings.
Procedures developed to effect
cyclopentannulation transformations have generally relied on the application o f a three
carbon, bifunctional reagent. The intrinsic bifunctionality can be applied in selective and
general reactions toward substrates o f diverse electronic nature and substitution patterns.
Reagents that rely on the properties o f allylsilane functionality and the selectivity o f
Sakurai additions could prove to be very useful synthons.
Selectivity in Michael additions has been shown to proceed with a high degree o f
stereoselectivity in additions to sulfmyl cycloalkenones.22 Treatment o f enantiomerically
pure sulfmyl cyclopentenone, 59, with TiCU provides a reactive intermediate that is
selectively attacked by the sterically hindered allyl silane 60 preferentially anti to the ptolyl group (Scheme 18).23
19
Scheme 18
A similar approach has been used in methylenecyclopentannulation reactions.
The Lewis acid mediated conjugate addition o f the functionalized allylsilane 63 leads to
an
allylchloride
64
that,
under
basic
conditions,
cyclizes
to
assemble
the
methylenecyclopentane ring 65 (Scheme 19).24
EtAlCl
SPh +
Scheme 19
Investigations in our laboratories have focused, in part, on a tandem Lewis acid
mediated
Sakurai
addition/cyclization reaction
o f [2-(trimethylsilylmethyl)prop-2-
enyljtrimethylsilane, 57, with sulfmyl enones 59 and 66. Addition o f the bifunctional
reagent 57 should result in a stereoselective Michael addition to give the metallo-enolate
20
67 (Scheme 20).
Subsequent Pummerer-type rearrangement should result in the
formation o f the sulfenyl cation 68, which would be immediately attacked by the
remaining allyl silane to give the annulation products 69 and 70.
59 n = l
66 n = 2
O
C ^rTVJ
69 n = I
70 n = 2
Scheme 20
Achiral sulfmyl enones were prepared from the corresponding ketones 71a or
71b. Treatment o f cyclopentanone or cyclohexanone with sodium hydride for 16 to 20
hours followed by the addition o f methyl toluenesulfmate at 0 °C gives the P-ketotoluenesulfoxides 72a and 72b in moderate to good yield (Scheme 2 1).25 The sulfoxides
undergo a Pummerer rearrangement when treated with acetic anhydride and catalytic
21
methanesulfonic acid to yield the 2-tolylthiocycloalk-2-enones 73a and 73b.26 Oxidation
with m-chloroperbenzoic acid at -78 °C gives the desired sulfmyl enones 74a and 74b.27
1) NaH, Et2O
2)
^ y S O - 'T o l
v 'n
'T olS O 2Me
72a n : 1
72b n : 2
O
Ac2O, MeSO3H
CH2Cl2
O
MCPBA
-78 0C
' 'n
73a n : 1
73b n : 2
'n
74a n
74b n
1
2
Scheme 21
The synthesis o f (S)-(+)-2-(p-toluenesulfinyl)cyclopent-2-enone, 59, and (5)-(+)2-(p-toluenesulfinyl)cyclohex-2-enone, 66, was achieved according to the procedure o f
Posner and co-workers.28 Freshly distilled 2-bromocycloalk-2-enone ethylene ketal 75a
or 75b underwent lithium-halogen exchange when treated with zr-butyllithium at -7 8 0C
(Scheme 2 1).29 Transfer o f the extremely unstable lithio derivative into a solution o f (-)menthyl p-toluenesulfinate, 76, in THF gave the sulfmyl ethylene ketals 77a and 77b in
moderate yield. Deprotection occured upon exposure o f the ketal to anhydrous copper
sulfate in acetone to give the enantiomerically pure sulfmyl enones 59, and 66 in 50%
and 60% yield respectively from the bromoethylene ketals.
22
i) H-Buli, THF
-78 0C
r~ \
oOoO IlX•
Br
If SN
^Tol
ii)
75a n = I
75b n= 2
/
77a n = I
77b n = 2
0'
CuSO4 (anhyd.)
Acetone
59 n = l 50%
66 n = 2 60%
Scheme 22
Reaction
of
(S)-(+)-2-(/7-toluenesulfinyl)cyclohex-2-enone,
66,
with
allyl
bis(silane) 57 under a variety o f conditions, including an assortment o f Lewis acids, gave
no significant conversion to cyclized product. Lewis Acids that were used in an attempt
to improve the yield included Ti(O Pr)4, Ti(O Pr)ZClz, Ti(O Pr)Clg, SnCl4, SiCl4, ZnBrz,
Zn(OTf)z, TM SOTf and trifluoroacetic anhydride.
Optimized conditions involved the
complexation o f the sulfmyl enone 66 with TiCl4 at -7 8 0C in CHzClz. Slow addition o f
allyl bis(silane) 57 over a 30 minute period and warming the reaction to -25 °C for
several days gave a 5% conversion to cyclized product 70 (Scheme 23).
temperatures caused complete degradation o f the starting material.
Elevated
23
SiMe3
ou
TiCl4
Q
66
S-jpTol
>
70
5%
57
Scheme 23
Treatment o f sulfmyl enone 59 with TiCl4 under the optimized reaction conditions
described for the formation o f 70 gave a 55% isolated yield o f cyclized product 69 after
only two days at -25 0C (Scheme 24). Inclusion o f trifluoroacetic anhydride at -7 8 0C,
after the addition o f the bis allyl(silane) 57 to the titanium complexed sulfmyl enone,
presumably facilitated the Pummerer rearrangement to form the sulfenyl cation
intermediate 68, allowing the reaction to proceed at -7 8 0C. However, the yield o f the
reaction was not improved providing 69 in 52% yield.
59
57
55%
Scheme 24
69
24
Pentenolide sulfoxide 81 and butenolide sulfoxide 85 were prepared as racemates
according to the procedure o f Posner and co-workers through a series o f oxidations and
Pummerer rearrangements (Scheme 25).30
O
D LH M D S
°
O
,
O
1) LHMDS
0V - J 2)TolSSO 2Tol 0X__J STol
78
79
2)
STol
O
TolSSTol
82
83
1) MCPBA
2) Ac2O
MCPBA
O
SToI
85
STol
MCPBA
84
Scheme 25
The sulfoxides 81 and 85 were subjected to the optimized reaction conditions as
described for the synthesis o f the thiopentalenes 65 and 70. Analysis o f the crude product
mixtures showed the consumption o f starting material and suggested that cyclization had,
to some extent, taken place (Scheme 26).
Attempts to isolate and characterize the
multiple products o f the reaction were unsuccessful due to the high instability o f the
materials.
25
Q
CTn I
TiCl4, CH2Cl2
-78 —
81 n = I
85 n = 2
-25 0C
57
86a n = I
86b n = 2
Scheme 26
Cyclopent-2-enone 25 and cyclohex-2-enone 87 were subjected to the reaction
conditions as a control in order to determine if the sulfmyl moiety was necessary for
cyclization to occur (Scheme 27). The treatment o f the enone 25 or 87 with TiCl4 at -78
°C followed by the addition o f allyl bis(silane) 57 generated the diketones 88a and 88b,
respectfully, in good yield.
No cyclized material was detected by GLC or GCMS
techniques.
O
A
,0
25 n = I
87 n = 2
TiCl4
*
”
CH2Cl2
-78 0C
O
O
A A
<VJL
&
88a n = I 75%
88b n = 2 82%
Scheme 27
This finding also suggested that a two step annulation process to give cyclized
products based on allyl bis(silane) additions to enones would be difficult in that
dimerization to give 88a or 88b would predominate.
Instead, a reagent bearing
26
synthetically complementary functionality, 58, would allow for increased control in the
reactivity o f one allylic moiety versus the other.
The introduction o f an ally! silane
function to electrophilic substrates and oxidative ring closure could then be achieved in a
tandem or stepwise reaction pathway to give cyclized products 90 (Scheme 28).
Scheme 28
Bifunctional Reagents
Development o f [2-(metallomethyl)prop-2-enyl]trimethylsilanes.
Allyl silanes have become invaluable tools for effecting selective synthetic
transformations.
Generation o f a reactive metallo-allyl silane would be an effective
means for introducing ally! silane functionalized moieties. The most direct route toward
implementing an efficient means of selectively forming carbon-carbon bonds while
minimizing potential for competitive Wurtz coupling in the formation o f [2(trimethylsilylmethyl)prop-2-enyl]lithium, I, was envisaged through the exchange o f
organometallics with alkyl lithium reagents (Scheme 29).
27
SiMe3
SiMe3
40 R = W-Bu3Sn
91 R = W-BuTe
92 R = MeSe
I
Scheme 29
Allylstannanes have been shown to undergo efficient transmetallation reactions
when treated with w-butyllithium.31
Prior to this research, the synthesis o f [2-
(trimethylsilylmethyl)prop-2-enyl]tri-w-butylstannane, 40, to our knowledge, had not
been reported. Efforts to prepare 40 through the reaction o f tri-w-butylstannyl lithium
with 43 or 93 resulted in moderate conversion to the desired allylstannane 40 along with
a substantial amount o f the coupling product 94 (Scheme 30). The separation o f the two
compounds could not be achieved through practical techniques.
Tellurium reagents have also been shown to undergo exchange with alkyllithium
reagents to generate reactive intermediates.32 Treatment o f 43 or 93 with W-BuTeLi
afforded 91, which was again contaminated with significant amounts o f the byproduct 94
(Scheme 30).
28
91
Scheme 30
In addition to the work of Majetich and co-workers15 it has been reported that
reaction
of
allyl
chloride
63
with
tri-H-butylstannyllithium
provides
[2-
(trimethylsilylmethyl)prop-2-enyl]tri-Az-butylstannane, 40, in acceptable yield with no
evidence o f the coupling biproduct 94 (Scheme 3 1).33 Allylstannane 40 was shown to
react under harsh conditions, either refluxing benzene or toluene, with acid chlorides or
aldehydes respectively to furnish allyl silanes 95 and 96 in moderate to good yields.
29
O
RA C,
Benzene (reflux)
Cl (Zi-Bu)3SnLi
SnwBu.
R
SiMe3
95
52 - 92%
SiMe3
O
63
RA H
OH
Toluene (reflux)
r
^
R
SiMe3
96
69 - 96%
Scheme 31
In 1984, K rief and Clarembeau illustrated the ability o f allylselenides, such as 97,
to undergo efficient transmetallation reactions when treated with alkyllithiums (Scheme
32).34
The reaction was found to be selective and not complicated by metallation
suggesting that alkyllithium reagents react with allylselenides as nucleophilic rather than
basic reagents.
30
100
27%
101
49%
Scheme 32
Reaction o f methylselenolithium with allylbromide 93 again produced substantial
quantities o f the coupling product 94 that was very difficult to separate from the desired
material through practical techniques (Scheme 33).
Treatment o f the easily obtained
mesylate 10335 under identical conditions resulted in the orderly formation o f [2(trimethylsilylmethyl)-2-(methylseleno)]prop-l-ene, 92.
observed.
The byproduct 94 was not
31
CH3Li
Se ------------CH3SeLi
THF, -78 0C
CH3SeLi
SiMe3
93
X ^O H
SiMe3
102
THF, -78 0C
MsCl, E t3N
CH2Cl2, 0 °C
92%
J ^ /O M s
I
SiMe3
CH3SeLi
JL ^S eO L
THF, -78 0C SiMe3
103
90%
92
Scheme 33
With an efficient synthesis o f the allylselenide 92 achieved, the capabilities o f this
new reagent were investigated.
Allylselenide 92 underwent efficient Li-Se exchange
when treated with M-BuLi at -78 0C furnishing [2-(trimethylsilylmethyl)prop-2enyl]lithium, I.
Addition o f iodododecane, 104, to the allyllithium I gave a clean
conversion to allylsilane 105 in 83% isolated yield.
Representative oxiranes, ketones,
and enones also reacted cleanly to providing 2-substituted allylsilanes (Table I).36
32
Table I. Reaction of I with Representative Electrophiles.
Electrophile
Product
Yield (% )a
^S iM e 3
M-Ci2H25I
83
12
104
105
O
.SiMeS
94
H3C ^ a
106
0 H 107
OH ,I
93b
109
(cis.trans = 1.5:1)
Oo
no
Y
O O ^ S iM
85
e 3
111
CC
^
a
112
TJ
95c
O
r\
114
N^CH3
Ph^H
116
N ^Ph
xC118h
113
OH ||
3
92
115
H3C NH Ii
PhC x xC ^ S i M e 3
90
117
P l C xNH Ii
" x C x C L ^ SiMe3
87
119
a Isolated yield. bConbined yield o f purified alcohols [Isolated yields:
109ac„ (56%); 109b lrans (37%)]. c Coirbmed yield of purified alcohols
[Isolated yields: stable diastereomer(63%); labile diastereomer (32%)].
33
The order o f addition o f the reagents proved crucial to the efficiency o f the
process and the purity o f the reaction products. Addition o f the substrates HO, 112,114,
116 and 118 to a solution o f the allyllithium in THF appeared to give the desired result by
examination o f the crude material. The products quickly decomposed or isomerized to
vinyl silanes before or during the work-up process.
many modes o f addition were investigated.
In order to remedy the problem,
It was found that a rapid transfer o f the
preformed organolithium reagent I in THF at -7 8 0C through a short cannula into a
solution o f the desired electrophile in THF at -7 8 °C resulted in the formation the desired
allylsilane adduct that could then be easily isolated and characterized.
Several aspects o f the reactivity o f the new reagent warrant mention.
The
addition o f I to propylene oxide, 106, gave the alcohol with excellent regioselectivity
resulting from the epoxide opening at the least hindered position. The new reagent also
reacts with cyclohexene oxide, HO, selectively to give only the /raws-alcohol 111.
Treatment o f conformationally biased 7-butyl cyclohexanone, 108 gave the alcohols 109a
and 109b in good yield as a mixture o f stereoisomers with attack occuring preferentially
from equatorial approach.
Unlike many other reagents, such as Grignards or other
organolithiums, exclusive 1,2-addition is observed through the treatment o f enones 112
and 114 with the new reagent I. The stereoselectivity is poor with respect to existing
stereocenters such as that present in (/)-carvone, 112, giving predominantly the Transadduct in 63% isolated yield with the alternative diastereomer being quite unstable, to the
point that isolation and characterization could not be achieved. Allyllithium I reacted
34
with imines effectively to give amines 117 and 119 in excellent isolated yield with no
evidence o f side reactions resulting from metallation o f the imine.
Conjugate Addition o f Allyllithiate I and Oxidative Ring Closure
The demonstrated utility o f [2-(trimethylsilylmethyl)prop-2-enyl]lithium,
I,
prompted the investigation o f new modes o f reactivity. It has been observed that silyl
enol ethers 120 react with allylsilane 121 under oxidative conditions to give addition
products 122 (Scheme 34).37 Conjugate addition o f 58 (M = Cu, Al, Zn, etc.) to enones
123 with trapping o f the resultant enolate by chlorotrimethylsilane (TMSCl) and
subsequent oxidative cyclization to procure products 125 would constitute an effective
means o f employing this method intramolecularly.
120
121
O
122
OSiMeq
a N +
TMSCl
VO(EtO)Cl2
SiMe3
SiMe3
123
58
O
124
Scheme 34
125
35
The observed stability o f allyllithium I suggested that transmetallation reactions
with copper salts could be achieved.
A recent report stated that iodotrimethylsilane
promoted the addition o f organocopper compounds to enones, esters and lactones. The
addition products o f these reactions could also be isolated as the silyl enol ethers 126
(Scheme 35).38 The reaction of allyllithium I under these conditions led to the formation
o f a compound that was tentatively assigned the structure 127 but could not be readily
isolated. The product mixture also contained a substantial amount o f ally! bis(silane) 57.
O
(i) RCu(LiI)-TMSI, -78 0C
O SM e 3
(H) E t3N, -78 0C
25
R
126
O SM e
(H) TMSI, 25
+
SM e3
S M e3
SM e 3
SM e 3
57
I
Scheme 35
The literature is rich in methods for the formation o f copper reagents.39 The
thermal instability associated with Gilman reagents (R2CuLi) bearing allylic ligands is
well documented 40 With a few exceptions, only one o f the two R groups is utilized in
synthetic applications thereby wasting the second equivalent o f the ligand, R
The
36
formation o f a mixed cuprate (RjR2CuXLi) that would selectively transfer only the ligand
o f choice, in this case I, would be ideal for our purposes.
Bertz and co-workers have suggested that ligands bearing P-silyl groups confer
thermal stability to the organocuprate and increase the reactivity and selectivity o f the
transferred ligand.41
Reaction o f copper iodide with trimethylsilylmethyllithium
(TMSMLi) and I according to the protocol described by Bertz and co-workers, appeared
to generate the mixed organocuprate (Scheme 36). The solution was homogenous and
the organocupratereacted efficiently with cyclopentenone at -78 °C. However, the 1,2- to
1.4- addition selectivity was poor giving mixtures o f the two adducts 128 or 129 and 130a
or 130b respectively. Optimization o f this procedure did result in the formation o f the
1.4- addition product selectively, although isolation as silyl enol ethers was problematic
giving less than 50% yield o f the products 128 or 129 after distillation.
(i) TMSMLi THF
CuI
(H )I
(iii) TM SCi HMPA
(iv) Enone
128 n = I
129 n = 2
<50%
130a n = I
130b n = 2
Scheme 36
Precedence in the literature for the conjugate addition o f copper reagents
facilitated by TMSCl is abundant.42
The effect o f N,N,N’,N ’-tetramethylendiamine
(TMEDA) on the promotion o f organocopper reactions with enones has also been shown
37
by Johnson and Marren43 to play a significant role in facilitating conjugate addition.
TMEDA was observed to stabilize and solubilize copper reagents while at the same time
increase the reactivity o f the organocopper reagent.
Accordingly, the combination o f
TMEDA and TMSCl enhanced the yields and reactivity o f organocopper reagents
providing a direct route to the formation o f silyl enol ethers.
Along these lines, addition o f the pre-formed allyllithium I to copper iodide
dissolved in a solution o f TMEDA and THF followed by the addition o f TMSCl and then
enone resulted in good conversion to the silyl ethers.
An inverse addition protocol
involving addition of I to the copper/TMEDA solution, followed by TMSCl and
immediate introduction o f the enone gave surprisingly good yields o f the silyl ethers 128
and 129 (Scheme 37).
The purification procedure was completed with a DMSO
extraction technique as outlined by Johnson and Marren giving products that were very
clean by 1H N M R1 >90%, and could be easily distilled or used without further
purification.
OSiMe3
Li
SiMe3
(i) CuI, TMH
9
(Ii)TM SQ
I
^
Scheme 37
Having achieved an efficient means o f generating the silyl enol ethers 128 and
129,
the
oxidative
cyclization
was
attempted
with
the
distilled
products.
38
Dichloroethoxyoxovanadium(V), was prepared by the reaction o f trichloroxovanadium
with ethanol according to the proceedure o f Hirao and co-workers, and purified by
distillation.44 Addition o f the silyl enol ethers 128 and 129 to a solution o f this reagent in
methylene chloride at -7 8 °C resulted in no reaction. Warming the solution also gave no
evidence that the desired reaction had occurred. After allowing the mixtures to stir for
several days at room temperature, only moderate conversions were realized (Scheme 38).
OSiMe3
(BO)VOCl2
CH2Cl2
’
128 n = I
129 n = 2
O
J
131 n = I (20%)
132 n = 2 (15%)
Scheme 38
Trimethylsilyl triflate (TMSOTf) has been shown to facilitate oxidative coupling
reactions o f silyl enol ethers and allylsilanes.45 The pretreatment o f the ethoxyvanadyl
(V) reagent with TM SOTf did little to stimulate the reactivity allowing for only slightly
improved yields with identical reaction times. The effect o f ligands on the reactivity o f
oxovanadium (V) reagents is an area that has remained unexplored with a few
exceptions.44 The introduction o f a ligand which could pull electron density away from
the metal center should facilitate the oxidizing properties o f the metal.
Reaction of
trifluoroethanol (TFE) with VOCI3 in hexane under similar conditions for the formation
39
o f (EtO)VOCb, provides a new reagent, dichloro(2,2,2-trifluoroethoxy)oxovanadium(V),
133.
Addition o f silyl enol ethers 128 and 129 to a solution o f the new vanadyl ester
133 in methylene chloride gave clean conversion to cyclized products at -7 8 °C and in
less than 30 minutes. The products 131 and 132 could be easily isolated in good yield
(Scheme 39).
OSiMe3
(TFEO)VOC i 2
I
C
H
2
Q
2 ;
SiMe3
. 78 °C 30 min
131 n = I (88%)
132 n = 2 (85%)
128 n = I
129 n = 2
Scheme 39
W ith the grounds for an efficient five-membered annulation process in hand, the
task o f establishing the generality o f the overall conjugate addition-cyclization process
was undertaken.
A number o f substrates were subjected to the reaction conditions
previously described for the formation o f silyl enol ethers with varying degrees o f
success. It was observed that substitution and ring size played and important role in the
effective transformation o f enones under optimized conditions.
2-Methylcyclopent-2-
enone, 134, (R)-(-)-carvone, 112, and coumarin, 137, react smoothly under the conditions
described for the formation o f 131 and 132 (Scheme 39) to give the silyl enol ethers 135,
136 and 138, respectively in a high state o f purity, >90% by 1H NMR (Table 2).46 The
spectrum o f silyl enol ether 136 suggested the formation o f a single diastereomer.
40
Table 2. 1,4-Addition of [2-(MetaIIomethyl)prop-2-enyl]trimethylsilanes to Enones.
O SM e
(i)»-BuLL THF, -78 0C
SeMe (H)CuLTMEDA, THF
(iii) TMSC1, Enone
Enone
Yield
Product
O SM e
135
O SM e
S M e1
112
97
136
J l^ S M e 3
O ^O
137
O
O SM e3
138
* Products were determined to be >90% pure by 1H NMRand were not
fully characterized
Attempts to purify the silyl enol ethers by distillation resulted in decomposition.
Therefore, the crude materials were subjected to cyclization protocol mediated by the
new vanadyl ester 133. The results for the overall process o f conjugate addition and
oxidative cyclization utilizing the new vanadyl ester 133 are assembled in Table 3.
41
Table 3. Oxidative cyclizations of 3-[2-(trimethylsilylmethyl)prop-2-enyl silyl enol
ethers by dichloro(2,2,2-trifluoroethoxy)oxovanadium(V).
I,
siM e3
92
(i)/7-BuLi, T H F,-78 0C O S M e 3
SeMe (“) CuI, IM ED A, THF j . R
(m) TMSCl Ehone
O
(IFEO )V O C i 2
S M e3 CH2C12j . 78 °c
30 min
a) Yield is calculated over two steps based on corresponding
starting enone.
42
The novel two-step process described above provides an efficient means o f
forming functionalized cyclopentane rings.
O f importance is the observation that 2-
substituted enones participate efficiently in the cyclopentannulation process. Indenone
140 was recovered as a single diastereomer.
The stereochemistry was determined
through NMR experiments. In difference NOE experiments the two methyl groups were
irradiated separately and gave reasonable signal enhancements to each other and to the
adsorption due to the proton at the ring junction (Figure 4).
Treatment o f 3-methylcyclohex-2-enone, 114,
isophorone, 142, (+)-pulegone,
143, 2-cycloheptenone, 144„ and 3-methylcylopent-2-enone, 145, with the allyl copper
reagent described above formed primarily 1,2-addition products (Scheme 40).
The
preference for 1,2- versus 1,4-addition may be alleviated with pretreatment of the enone
with a Lewis acid such as BF3Et2O.47
Under these conditions 1,4-addition should
predominate although the isolation of silyl enol ethers would not be viable.
43
(i)n-BuLi, THF,-78 °C
SeMe (U)CuI, TMEDA, THF
SiMe3
(iii) TMSC1, Enone
HO
SiMe 3
v
R
92
Enone
Scheme 40
The importance o f the allylically-disposed trimethylsilyl substituent in facilitating
the disfavored 5-endo-trig mode o f cyclization was examined in the reaction o f silyl enol
ether 148 with (TFEO)VOC i2, 133 (Scheme 41). Slow addition o f a solution of the silyl
enol ether 148 in CH2Cl2 to the vanadyl ester 133 at -78 °C provided a complex mixture
o f products.
The major components were tentatively assigned as the isomeric 1,4-
diketones 149 based on GCMS and NMR data for mixture o f diastereomers. This finding
is consistent with the postulate that a 5-endo-trig mode o f cyclization would be
disfavored as well as the intermediacy o f an a-carbonyl radical intermediate.
44
MeSeLi
” ~
THF, -78 0C
(i) M-BuLi, THF, -78 0C
Il
(ii) CuI, TMEDA THF
M eS e^L j
146
OTMS
(iii) TMSCf Enone
147
(TFEO)VOC i 2
Scheme 41
Alternatively, exposure of 151 to the vanadyl ester 133 under identical conditions
led to a smooth 5-exo-trig cyclization giving a mixture o f the pentalenones 152a and
152b in 65% combined yield (Scheme 42).
45
\
+
ciMg/ ' ' ^ y '
CuIZIMEDA (5%)
TMS C I, THF
126
150
OTMS
'/ /
151
(TFEO)VOC i 2
CH2Cl2, -78 °C
Scheme 42
These results tend to support the proposed mechanism for the oxidative
desilylation o f silyl enol ethers by the oxovanadium reagent to form an a-keto radical
155 (Scheme 43).37 The radical can then be trapped by olefins, other silyl ethers or
allylsilanes. Additions o f allylsilanes proceed regioselectively to form the radical (3 to the
trimethylsilyl group. Further oxidation and desilylation leads to the formation o f 158.
Scheme 43
46
Oxidative Coupling o f Silyl EnolEthers
There are few procedures in the literature that are useful for the synthesis o f
unsymmetrical 1,4-diones. Moderate success has been achieved through reaction o f the
a-radical o f stannane 159 and electron rich olefins such as silyl enol ether 160 (Scheme
4 4 ) 48 An interesting aspect o f this reaction is the refined logic behind the process.
Through cyclic voltammetry, it was determined that the oxidation potential o f the <xstannyl alkanoates would allow for selective formation o f the cc-stannyl radical in the
presence o f silyl enol ethers.
OSi(tBu)Me2 CAN, CH3CN
(nBu)3S n ^ C O 2CH2Ph + = K x
Ph
-23 — rt, 18 h
159
160
86%
CO2Bn
161
Scheme 44
The oxidative desilylation o f silyl enol ethers has been reported to be a
moderately effective means for selective formation of unsymmetrical 1,4-diketones
(Scheme 45).49 The combination o f silyl enol ethers is limited in that the silyl enol ethers
utilized as radical sources, 163 and 167, require a higher degree o f substitution than those
employed as radical acceptors, 162, since the former must be oxidized more easily than
the latter.
47
O SM e3
O
OSiMe3 VO(EtO)Cl2 (3 eq) X / \ . P h
6*^
162
163
CH2Cl2, -78 °C
3h then -30 °C, 4h
O
O
U S
164
68%
165
3%
166
Trace
Scheme 45
As a comparative study, the reactants 162 and 167 were added to a solution o f
(TFEO)VOCb, 133, in CH2Cl2 at -78 0C (Scheme 46). In this environment the reaction
was complete within a few minutes after addition o f the silyl enol ethers. The yield o f the
reaction was greatly improved through the slow addition, over a 30 minute period, o f the
silyl enol ethers to a solution of the vanadyl ester 133 in CH2CI2 It was also observed
that only 2 equivalents o f the vanadyl ester 133 was needed to effect the desired
transformation.
48
Scheme 46
The new vanadyl ester 133 also proved quite effective in the cross-coupling o f the
silyl enol ethers 170 and 167 (Scheme 47), again allowing for the highly selective
formation o f the unsymmetrical 1,4-diketone 171 and utilizing only 2 equivalents o f 133.
O
OSiMe3 0SiMe
O
O
3 VO(EtO)Cl2 (3 eq)
+ ^ 'B u
170
167
CH2Cl2, -78 °C, 3h
then -30 °C, 4h
O
171
58%
172
32%
169
Trace
OSiMe
'Eu
'Eu
6+
170
169
0%
Scheme 47
The attempted cross-coupling reaction o f silyl ethers 170 and 162 met with
moderate success (Scheme 48). To achieve any selectivity at all in this reaction, in which
49
the oxidation potentials for the reactants must be very close, supports the effectiveness o f
the new vanadyl ester 133 in oxidative coupling reactions.
OSiMe3
I
6
170
-
OSiMe3
JL
6
162
(TFEO)VOC i 2 (2 eq)
---------------~
CH2Cl2, -78 0C
30 min
9
9
( T T I
V _/
+
165
+ 172
4: 2: 1
Scheme 48
Homo-coupling reactions o f the simple silyl ethers 162 and 167 have proven
difficult with (EtO)VOCb (Scheme 49).
Alternatively, addition o f 162 or 167 to a
solution o f (TFEO)VOCb in CHzCb provided the 1,4-diketones 165 and 169 in excellent
isolated yield (Scheme 50).
OSiMe3
A
C
162
OSiMe3
A.B
u
167
(EtO)VOCl2 (2 eq)
O
O
CH2Cl2, -78 0C, 3 h
then -30 0C, 4 h
(EtO)VOCl2 (2 eq)
CH2Cl2, -78 0C
2 h, rt 12 h
Scheme 49
O
169
11%
50
OSiMe3
6
162
OSiMe3
167
(Tf e O)VOCI2 (2 eq)
0
CH2Cl2, -78 0C
30 min
(TFEO)VOC i 2 (2 eq)
X
-------------------- 'Eu
CH2Cl2, -78 °C
30min
0
165
93%
/y s u
0
169
62%
Scheme 50
The results presented here demonstrate that (TFEO)VOClz, 133, is a superb
reagent for one-electron oxidation reactions o f silyl enol ethers in intramolecular
additions to allylsilanes and the formation o f symmetrical and unsymmetrical 1,4diketones. The reagent possesses the ability to effect these transformations under mild
conditions with a high degree o f selectivity.
51
Attempted Synthesis o f (±)Pentalenic Acid
Interest in methodologies applicable to the preparation o f cyclopentanoid
compounds have been fueled by the difficulties encountered in the construction o f these
very rigid and highly functionalized ring systems. Sesquiterpenoid metabolites having a
tricyclo[6.3.0.0]undecane skeleton are present in plant, marine and microbial sources.
Many members o f the polyquinane families exhibit significant biologic activity.
The
biologically most important terpenes are those found in the hirsutane and pentalenane
families o f compounds. Pentalene, 174, and pentalenic acid, 5 and deoxypentalenic acid,
175, belong to a class o f nonlinearly fused triquinanes isolated from the broth of
Streptomyces griseochromogens (Figure 5).50 These compounds have been shown to
play a role in the biosynthesis of o f the antibiotic pentalenolactone 1 7 6 /'
Another
related sesquiterpene, deoxypentalenic acid, 175, has displayed anti-tumor activity
against sarcoma 180 in mice.^
5
Figure 5. Pentalene n a tu ra l products
176
52
The structural similarities o f 174, 5 and 175 would suggest a common
intermediate that we envisioned could be the ketone 177 (Scheme 51). Retrosynthetic
annalysis o f the target revealed that the angularly fused triquinane could be obtained
through
a
tandem
2-propylidene-l,3-bis(silane)
photocycloaddition/fragmentation
sequence from allyl bis(silane) 180
177
178
Scheme 51
The synthesis o f the photocyclization precursor 180 might be achieved through
the coupling o f the allyl bis(silane) 182 or 183 with 4-dimethyl-2-cyclopentenone, 181, or
by the elaboration o f enone 184 by the procedures developed by Kercher and
Livinghouse for the introduction o f allyl bis(silane) functionality (Scheme 52).53
53
183 X = I
Scheme 52
The synthesis o f halides 182 and 183 was accomplished in a straightforward
manner. Alcohol 185 was prepared nearly quantitatively from 5-methyl-4-hepten-2-one
by sodium borohydride reduction followed by protection o f the alcohol as the pivalate
186 (Scheme 53).
Exposure o f the aldehyde 187 obtained from ozonolysis o f 186 to
carbon tetrabromide and triphenylphosphine yielded the divinyl bromide 188 in 60%
(unoptimized) yield. The ally! bis(silane ) 189 was obtained upon coupling o f 188 with
(TMSM)2Zn under the Kercher and Livinghouse protocol.53 Bromide 182 and iodide 183
were easily prepared through deprotection and halogenation o f 189 (Scheme 54).
54
PivCl
OH
i)0 3
Pyridine
97%
185
Br
OPiv
Br
188
OPiv
CBr4, PPh3
ii) SMe2 0Piv
187
85%
186
(TMSM)2Zn
Pd(PPh3)2Cl2
60%
SiMen
. s .Me3
OPiv
90%
189
Scheme 53
SiMe3
SiMe3
182
1) LAH
2) M sCLEt3N
1) LAH
SiMe3
189
3) LiBr, HMPA
75%
2) PPh3
Imidazole, I 2
80%
SiMe3
183
Scheme 54
Exhaustive efforts to couple either 182 or 183 with enone 181 led to the
realization that the presence o f allyl bis(silane) functionality would not be tolerated under
conditions needed to effect the transformation (Scheme 55). The addition o f a mixture o f
the bromide 181 and 182 to lithium powder in diethyl ether with ultrasonic irradiation54
resulted in the complete destruction o f all starting materials and no detectable amounts o f
the desired product 190. Attempts to form Grignard reagents, for use in cerium mediated
additions, from 182 or 183 yielded desilylated and dehalogenated material.
55
Li, Ultrasound
SiMei
181
or
M g CeCl3
SiMei
182 or 183
190
N ot Detected
Scheme 55
An alternate route involved the coupling the secondary bromide 191 with the
enone 181 followed by an oxidative rearrangement to give the enone 192 (Scheme 56).55
Treatment o f the crude aldehyde resulting from the ozonolysis o f 192 under the
conditions previously described for the synthesis o f allyl bis(silanes) yielded the precycle
180.
I ) Li, Ultrasound
OH
2) LiBr, DMF
185
91%
Br
'
191
2) CBr4, PPh
79%
Scheme 56
2) PCC, Florosil
181
78%
56
Irradiation o f 180 in degassed benzene, methylene chloride, acetonitrile and
hexane generally led to either no reaction or desilylation o f the starting material (Scheme
57).
The inclusion o f CuOTf has been shown to facilitate photoinitiated [2 + 2]
cycloadditions through binding of the metal to the alkene, thereby creating a
chromophore which is then able to accept a photon and increase the reactivity o f the
alkene moiety.56
Addition o f CuOTf to solutions o f 180 in degassed benzene or
methylene chloride, resulted in the degradation o f the bis allyl(silane) functionality.
Wavelengths >290 nm have been shown by Crimmins and co-workers to effect
secondary cleavage o f photolytic precursors o f the natural products 174, 5 and 175.57
The use o f Uranium filters (X > 350 nm) however, allowed for efficient photocyclization
with excellent selectivity (Scheme 58).
57
73%
Scheme 58
In a personal communication with Prof.
Crimmins, it was learned that
cyclopentenones are very unreactive under these conditions and the presence o f a-ester
functionality sufficiently activated the system to allow the cyclization to occur at lower
energies (X > 350 nm). However, derivatization o f the Crimmins enone 199 to give 200
has yet to be accomplished.
Scheme 59
Enone 180 was reacted with various Lewis acids in an attempt to achieve
cyclization through Sakurai addition o f the allylsilane functionality (Scheme 60).
We
58
hoped to either isolate the addition product 201 or transform the allyl silane in situ or
through subsequent oxidative cyclization to give the tricycle 177 directly.
S iM e 3
L ew is A cid
Scheme 60
O f the Lewis acids used in an attempt to realize these goals (including Me2AlCl,
MeAlCl2, (TFEO)VOC i2, TMSOTff(TFEO)VOCl2, AgOTff(TFEO)VOCl2, Ti(O1Pr)4,
Ti(O Pr)2Cl2), TiCl4 proved to be the only one that gave any conversion to the desired
material 201. Treatment o f a solution o f 180 in CH2Cl2 at -78 0C with TiCl4 provided
201 (as a tentatively assigned structure) in 63% yield as an extensive mixture of
inseparable diastereomers. Fluoride ion sources such as TBAT,58 TBAF,59 have also
been used to promote inter- and intramolecular Michael additions o f allylsilanes.
However, allyl bis(silane) 180 proved to be quite inert to these relatively harsh
conditions.
The preliminary results o f the attempted synthesis o f pentalenic acid are
encouraging. The introduction o f ester functionality, as in 200, through the procedure o f
Crimmins and co-workers57 should facilitate photocyclization to give 203 (Scheme 61).
59
The presence o f the new functional group may also encourage future attempts to effect
fragmentation/cyclization transformations to give the valuable intermediate 177.
CO2Me
^ = - C O 2Me
201
MgCl
202
Scheme 61
60
SUMMARY
The selective formation o f carbon-carbon bonds with the introduction o f
allylsilane functionality utilizing a new trimethylenemethane synthon 92 has been
achieved. W ith this new reagent, the possibilities o f selective bond formation through the
exploitation o f the bifimctionality o f the synthon can be explored.
The synthetic
elaboration o f 92 in the development o f novel oxovanadium (V) ring formation protocol
has been shown to be a versatile process that should prove useful in future synthetic
strategies with the aim o f method development or natural product synthesis.
The
discovery o f dichloro(2,2,2-trifluoroethoxy)oxovanadium and the properties the reagent
has displayed in selective oxidative coupling reactions should supply new and exciting
means o f completing difficult transformations.
The attempted synthesis o f pentalenic acid has allowed for the exploration o f allyl
bis(silane) reaction terminators. These functionalities are surprisingly stable to a variety
o f reactive media.
W ork is continuing on this project with the hopes o f achieving
synthetically useful intermediates through the elaboration o f allylsilane functionality.
61
EXPERIMENTAL SECTION
General Experimental Details
1H NM R and 13C NM R spectra were recorded on a Broker 300 or 250 MHz
spectrometer with chemical shifts reported as 5 values in ppm relative to the residual
proton signals in CDCl3 or C6D6 (1H 6 = 7.24 or 7.15) or the CDCl3 or C6D6 triplet (13C 8
= 77.0 or 128.7) unless otherwise stated. Coupling constants (J) were reported in Hz.
Infrared spectra were recorded on a Broker ISF 25 spectrometer.
Reactions were
monitored by gas chromatography (GLC) on a Hewlett Packard 5890 Series II or a
Varian 3700 gas chromatograph with Alltec Econocap SE 54 column (15 m, 0.54 mm id)
and temperature programming. High resolution mass spectra were recorded on a VG
instruments 70E-HF spectrometer. Thin layer chromatography (TLC) was performed on
SILGZUv 254 plates supplied by Alltech.
Solvents used as reaction media were distilled immediately before use.
Tetrahydrofuran (THF) and diethyl ether (E t20) were distilled from sodiumbenzophenone ketyl immediately before use. Methylene chloride (CH2Cl2) was distilled
from P2O5 prior to use. Solutions o f M-butyllithium (M-BuLi) in hexanes were titrated
with 2-butanol (2.00 M in ethylbenzene) in ether at 0 °C with 2,2-bipyridal as an
indicator.
KOH.
Copper
Tetramethylethylendiamine (TMEDA) was distilled from and stored over
Chlorotrimethyl silane (TMSCl) was distilled from and stored over sodium.
(I)
iodide
was
purified
according
to
a
published
procedure.60
Trichlorooxovanadium (V) was purchased from Strem Chemical Co. and used without
further purification.
62
The following materials were prepared according to literature methods: (S)-(+)-2(p-toluenesulfinyl)cyclopent-2-enone, 59, and (S)-(+)-2-(p-toluenesulfinyl)cyclohex-2enone,
66,28
[2-(trimethylsilylmethyl)prop-2-enyl]trimethylsilane,
(bromomethyl)prop-2-enyltrimethylsilane,
92,
and
57,21
2-
2-(bromomethyl)prop-2-
enyltrimethylsilane 93,35 2-(trimethylsilylmethyl)prop-2-enyl methane sulfonate, 103/'
N-benzylidine methyl amine, 116, and N-(2-methylpropylidine)-benzilamine, 118 " Silyl
enol ethers 162,167 and 170 were prepared from the corresponding ketone.62
Allyl bis(silane) tandem addition/cycloaddition
cz"5-Hexahydro-5-methylene-6a-(p-touenelthio)-1(2//)-pentalen-1-one, 69.
O
Q fTr.1
A 100 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream of argon. Titanium tetrachloride (0.045 ml, 0.41mmol,
1.0 equiv) was added via syringe to a stirred solution of 59 (90 mg, 0.41 mmol) in
dichloromethane (2.5 mL) at -78 °C.
After stirring at -7 8 °C for 20 min 2-
trimethylsilylmethyl allyltrimethylsilane, 57, (107 mg, O.53mmol, 1.3 equiv) in
dichloromethane (2.5 mL) was added dropwise over I hour. After stirring for 2 hours at
-7 8 °C the mixture was warmed to -25 °C and stirred for 48 hours. The mixture was
then transferred via cannula and argon pressure into saturated aqueous sodium
bicarbonate solution (10 mL). The layers were separated and the aqueous solution was
extracted with dichloromethane ( 2 x 3 mL). The organic layers were combined, dried
63
(M gS04), filtered and concentrated in vacuo.
The residue was purified by flash
chromatography (2.5 - 10% ethyl acetate/hexanes) affording 69 as a colorless oil (0.058
g, 55%): 1H NM R (CDCI3, 300 MHz) 5 7.34 and 7.09 (2 d, 4 H, J = 8 Hz), 4.82 (d, 2 H,
J = 13 Hz), 2.63 (m, 4 H), 2.32 (s, 3 H), 2.28 (m, I H), 2.08 (m, 2 H), 1.55 (m, I H); 13C
N M R (CDCI3, 75 MHz) 5 136.0 (CH), 129.6 (CH), 107.8 (CH2), 46.9 (CH3), 41.4
(CH2), 38.3 (CH2), 35.7 (CH2), 23.7 (CH2), 21.2 (CH); IR (Neat) 2951, 1733 cm"1;
MS (EI) 258, 202, 124, 79.
Alternate procedure for the preparation o f 69
A 100 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon. Titanium tetrachloride (.045 ml, 0.41mmol, 1.0
equiv) was added via syringe to a stirred solution o f 59 (90.2 mg, 0.41 mmol) in
dichloromethane (2.5 ml) at -78°C.
After stirring at -7 8 °C for 20 min 2-
trimethylsilylmethyl allyltrimethylsilane, 57, (107 mg, 0.53mmol,
1.3 equiv) in
dichloromethane (2.5 ml) was added dropwise over I hour. After stirring for 2 hours at 78 °C trifluoroacetic anhydride (86 mg, .041 mmol, 1.0 equiv) was added via syringe.
The mixture was stirred at -7 8 °C for an additional 30 min and transferred via cannula
with argon pressure into saturated aqueous sodium bicarbonate (10 ml). The aqueous
solution was washed with dichloromethane ( 2 x 3 ml).
The organic layers were
combined, dried (MgSC>4), filtered and concentrated. The product was purified by flash
chromatography (2.5 - 10% ethyl acetate/hexanes, silica) affording 69 as a colorless oil
(0.055 g, 52%)
cA-Hexahydro-2-methylene-3a-(p-toluenethio)-477-inden-4-one, 70.
64
A I OO mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon. Titanium tetrachloride (0.045 mL, 0.41 mmol,
1.0 equiv) was added via syringe to a stirred solution o f 66 (90 mg, 0.41 mmol) in
dichloromethane (2.5 mL) at -78 °C.
After stirring at -7 8 °C for 20 min 2-
trimethylsilylmethyl allyltrimethylsilane, 57, (107 mg, 0.53mmol,
1.3 equiv) in
dichloromethane (2.5 mL) was added dropwise over I hour. After stirring for 2 hours at
-78 °C the mixture was warmed to -2 5 °C and stirred for 48 hours. The mixture was then
transferred via cannula and argon pressure into saturated aqueous sodium bicarbonate
solution (10 mL). The layers were separated and the aqueous solution was extracted
with dichloromethane ( 2 x 3 mL). The organic layers were combined, dried (MgSOq),
filtered and concentrated in vacuo. The residue was purified by flash chromatography
(2.5 - 10% ethyl acetate/hexanes, silica) affording 70 as a colorless oil (6 mg, 5%): I H
NM R (CDCI3, 300 MHz) 5 7.23 and 7.08 (2 d, 4 H, J = 8 Hz), 4.82 (d, 2 H, J = 7 Hz),
3.26 (m, I H), 3.10 (m, I H), 2.67 (m, I H), 2.45 (m, 2 H), 2.31 (s, 3 H,), 2.22 (m, 3H),
1.95 (m, 2 H), 1.63 (m, I H);
NMR (CDCI3, 75 MHz) 5 135.3 (CH), 129.7 (CH),
107.0 (CH2), 48.0 (CH3), 42.1 (CH2), 37.2 (CH2), 35.8 (CH2), 24.1 (CH2), 22.6 (CH2),
21.2 (CH); IR (Neat) 2935, 1705 cm -1; MS (EI) 272, 149, 124, 91.
2-(Trimethylsilylmethyl)prop-2-enyllithium
2-(Trimethylsilylmethyl)-2-methylselenoprop-1-ene, 92.
65
SeCHg
SiMe3
A I OO mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon. Selenium powder (1.48 g„ 18.8 mmol) was
added and the flask was again carefully purged with argon whereupon THF (25 mL) was
added. Stirring was initiated and the slurry was cooled to -78 °C. A solution o f MeLi
(14.46 mL, 18.8 mmol, 1.30 M in E t20) was added dropwise until the selenium had
dissolved and a slight yellow color o f the CHgSeLi persisted over the red/brown colored
(CHgSe)2. A second 100 mL flask equipped with a magnetic stirring bar and septum was
flame dried under a stream o f argon. Mesylate 103 (4.17 g, 18.8 mmol) in THF (20 mL)
was added and the solution was cooled to -78 °C. The CHgSeLi solution in the first flask
was then transferred via cannula and argon pressure into the flask containing the mesylate
solution. The reaction mixture was allowed to warm and stirred for 30 min at 25 °C The
solution was diluted with ether (20 mL) and poured into aqueous, saturated sodium
bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with
ether (50 mL). The combined organic extracts were dried (K2COg) and concentrated in
vacuo. Distillation o f the residue afforded allyl selenide 92 as a colorless liquid (3.76 g,
90%, bp: 40-45 °C, 0.05 mmHg). 1H NMR (CDClg, 300 MHz) 5 4.67 (1H, app s), 4.58
(1H, app s), 3.08 (2H, s), 1.87 (3H, s), 1.66 (2H, s), 0.02 (9H, s); ^ C NMR (CDClg, 75
MHz) 6 148.5 (O), 110.6 (CH2), 33.6 (CH2), 25.1 (CH2), 4.5 (CHg), -1.0 (CHg); FTIR
(neat) 2954, 2923, 2359, 1623, 1418, 1247, 858, 840 c m '1; HRMS (PCI/CH4) calcd for
C gH igSi80Se (M+H)+ 222.0343, found 222.0343; calcd for C gH igSi78Se (M+H)+
220.0351, found 220.0344; calcd for C gH igSi76Se (M+H)+ 218.0370, found 218.0361.
66
2-(T rimethy lsily lmethyl)-pentadodec-1-ene, 105.
^ S iM e 3
W-H25C 12
A 10 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon, charged with THF (1.5 mL) and cooled to -78
°C. A solution o f n-BuLi (48 pL, 0.10 mmol, 2.11 M in hexanes) was then added via
syringe and the solution was stirred at -78 °C for 2 min. Allyl selenide 92 (22 mg, 0.10
mmol) was then added dropwise via syringe and the solution was stirred for 30 min at -78
°C. I-Iodododecane, 104, (25 pL, 0.10 mmol) was then added in one portion via syringe.
After stirring for 30 min at -78 °C the solution was allowed to warm to 25 °C. The
reaction mixture was quenched by the addition o f saturated, aqueous potassium
bicarbonate (2.5 mL). The aqueous layer was then extracted with ether ( 2 x 3 mL). The
combined ether extracts were washed with brine (3 mL), dried (K2CO3) and concentrated
in vacuo. Chromatography of the residue (5% Et2OZhexane, silica) afforded allyl silane
105 as a colorless oil (26 mg, 83 %). 1H NMR (CDCI3, 300 MHz) 5 4.55 (1H, app s),
4.48 (1H, app s), 1.92 (2H, t, J = 7.2 Hz), 1.50 (2H, app s), 1.42-1.37 (2H, m), 1.24 (20H,
br s), 0.86 (3H, t, J = 12.6) 0.01 (9H, s); 13C NMR (CDCI3, 75 MHz) 5 147.9 (Q , 107.0
(CH2), 38.7 (CH2), 32.3 (CH2), 30.1 (CH2), 29.9 (CH2), 29.8 (CH2), 28.3 (CH2), 27.2
(CH2), 23.1 (CH2), 14.5 (CH3), 0.9 (CH3); FTIR (neat) 2956, 2924, 2853, 1466, 1377,
1248, 838 c m '1.
HRMS (PCI/CH4) calcd for CigHqoSi (M+H)+ 296.2899, found
296.2909.
(±)-5-(T rimethy lsilylmethyl)-hex-5 -en-2-ol, 107.
67
SMe 3
OH
A 100 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream of argon, charged with THF (1.5 mL) and cooled to -78
°C. A solution o f M-BuLi (48 pL, 0.10 mmol, 2 .1 1 M in hexanes) was then added via
syringe and the solution was stirred at -78 0C for 2 min. Allyl selenide 92 (22 mg, 0.10
mmol) was then added dropwise via syringe and the solution was stirred for 30 min at -78
°C.
Propylene oxide, 106, (7.0 pL, 0.10 mmol) was then added in one portion via
syringe. After stirring for 30 min at -78 0C the solution was allowed to warm to 25 °C.
The reaction mixture was quenched by the addition o f saturated, aqueous potassium
bicarbonate (2.5 mL). The aqueous layer was then extracted with ether ( 2 x 3 mL). The
combined ether extracts were washed with brine (3 mL), dried (K2COg) and concentrated
in vacuo.
Chromatography of the residue (5% Et2OZhexanes with 0.1% Et3N, silica)
afforded allyl silane 107 as a colorless oil (17.5 mg, 94%). Spectral data were consistent
with that reported in the literature.63
Cz"5'-4-( I, I -dimethylethyl)-1-[(trimethylsilylmethyl)-prop-1-enyljcyclohexan-1-ol, 109a
TransA-{ I , I -dimethylethyl)-1-[(trimethylsilylmethyl)-prop-1-enyl]cyclohexan-1-ol,
109b
68
Al OO mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon, charged with THF (1.5 mL) and cooled to -78
°C. A solution o f M-BuLi (48 pL, 0.10 mmol, 2.11 M in hexanes) was then added via
syringe and the solution was stirred at -78 °C for 2 min. Allyl selenide 92 (22 mg, 0.10
mmol) was then added dropwise via syringe and the solution was stirred for 30 min at -78
°C. 4-(2,2-Dimethylethyl)-cyclohexan-1-one, 108, (77 mg, 0.50 mmol) was then added
in one portion via syringe. After stirring for 30 min at -78 °C the solution was allowed to
warm to 25 °C. The reaction mixture was quenched by the addition o f saturated, aqueous
potassium bicarbonate (2.5 mL). The aqueous layer was then extracted with ether ( 2 x 3
mL). The combined ether extracts were washed with brine (3 mL), dried (K2CO3) and
concentrated in vacuo.
Chromatography o f the residue (2% Et2OZhexanes, silica)
afforded alcohols 109a and 109b.64 109a as a colorless oil (79 mg, 56%).
NMR
(CDCI3, 300 MHz) 5 4.68 (1H, app s), 4.61 (1H, app s), 2.05 (2H, s), 1.67-1.65 (3H, m),
1.61 (2H, s), 1.56-1.54 (2H, m), 1.35-1.30 (5H, m), 0.84 (9H, s), 0.00 (9H, s); 13C NM R
(CDCI3, 75 MHz) 5 144.8 (Q , 111.5 (CH2), 70.5 (Q , 52.2 (CH2), 48.4 (CH), 38.6
(CH2), 32.8 (Q , 30.0 (CH2), 28.0 (CH3), 23.0 (CH2), -L I (CH3); FTIR (neat) 3455,
2952, 2867, 1457, 1365, 1247, 851 cm"1. 109b as a colorless oil (52 mg, 37%);
1H
N M R (CDCI3, 300 MHz) 8 4.72 (1H, app s), 4.64 (1H, app s), 2.17 (2H, s), 2.04 (1H, s),
1.78-1.66 (4H, m), 1.64 (2H, s), 1.44-1.35 (2H, m), 1.12-1.04 (3H, m), 0.84 (9H, s), 0.01
(9H, s); 13C NM R (CDCI3, 75 MHz) 8 145.0 (Q , 112.1 (CH2), 71.8 (Q , 47.8 (CH2),
44.0 (CH), 39.0 (CH2), 32.7 (Q , 29.6 (CH2), 28.0 (CH3), 25.0 (CH2), -0.9 (CH3); FTIR
(neat) 3455, 2952, 2867, 1457, 1365, 1247, 851 cm"1; HRMS (PCI/CH4) calcd for
C i7H 340S i (M-H)+ 281.2301, found 281.2292.
69
(±)-7’r ara-2-[2-(trimethylsilylmethyl)-prop-2-enyl]cyclohexan-l-ol, 111.
.OH
SiMe3
A 100 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon, charged with THF (2.5 mL) and cooled to -78
°C. A solution o f M-BuLi (24 pL, 0.50 mmol, 2.11 M in hexanes) was then added via
syringe and the solution was stirred at -78 °C for 2 min. The allyl selenide 92 (111 mg,
0.50 mmol) was then added dropwise via syringe and the solution was stirred for 30 min
at -78 °C. A second 10 mL flame dried flask was equipped with a magnetic stirring bar,
septum and purged with argon. Cyclohexene oxide (0.050 mL, 0.50 mmol) in THF (2.0
mL) was then added and the solution was cooled to -78 °C. The solution in the first flask
was then transferred via cannula into the second flask containing the cyclohexene oxide
solution. The reaction mixture was quenched after stirring for 15 min at -78 °C with a
solution ofEt3NH+*CH3C02- (0.8 mL, I M in THF). The reaction mixture was warmed
to 25 °C and was then diluted with ether (3 mL) and washed with water (5 mL). The
layers were separated and the aqueous layer was extracted with ether (2 mL).
The
combined organic solutions were washed with saturated, aqueous sodium bicarbonate,
dried (K2CO3) and concentrated in vacuo. Chromatography o f the residue (5%
Et2OZhexanes with 0.1% Et3N, silica) afforded the alcohol 111 as a colorless oil (92.5 mg,
85%).65 1H NMR (C6D6, 300 MHz) 6 4.83 (1H, app s), 4.74 (1H, app s), 3.09 (1H, ddd,
J = 13.8, 9.0, 4.2 Hz), 2.69 (1H, dd, J = 13.8, 4.5 Hz), 1.90-1.83 (2H, m), 1.77 (1H, dd, J
= 13.8,9.0 Hz), 1.62 (2H, d, J = 3.0 Hz), 1.59-1.43 (3H, m), 1.31-1.26 (2H, m), 1.24-1.09
(2H, m), 0.87-0.75 (1H, m), 0.14 (9H, s); 13C NMR (C6D6, 75 MHz) 5 147.5 (Q , 109.3
70
(CH2), 75.2 (CH), 43.7 (CR), 43.0 ( ( % ) , 36.2 (CH]), 31.1 (C R ]), 26.8 (C R ]), 26.1
(C R ]), 25.4 (C R ]), -1.0 (C R ]): FTIR (neat) 3353, 3071, 2926, 2855, 1630, 1448, 1247,
1058, 1034, 851 cm"1; HRMS (PCI/NH3) calcd for C i3H 260S i (M+H)+ 227.1831,
found 227.1822. The chemical shift of the a-proton (CJT-OH) to the hydroxyl group (^H
NMR 6 3.09) suggests only the trans isomer was form ed.^
5-(2-Methyl-1-ethenyl)-2-methyl-1-[((2-(trimethylsilyl)methyl)-prop-1-en]-cyclohex-2en-l-ol, 113.
A 10 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream of argon, charged with THF (2.5 mL) and cooled to -78
°C. A solution o f n-BuLi (24 pL, 0.50 mmol, 2.11 M in hexanes) was then added via
syringe and the solution was stirred at -78 °C for 2 min. Allyl selenide 92 (111 mg, 0.50
mmol) was then added dropwise via syringe and the solution was stirred for 30 min at -78
°C. A second 10 mL flame dried flask was equipped with a magnetic stirring bar, septum
and purged with argon. A solution of (R)-(-)-carvone 112 (63 pL, 0.40 mmol) in THF
(2.0 mL)was then added and the solution was cooled to -78 °C. The solution in the first
flask was then transferred via cannula into the second flask containing the carvone
solution. The reaction mixture was quenched after stirring for 15 min at -78 °C with a
solution ofEt3NH+*CH3C02 (0.8 mL, I M in THF). The reaction mixture was allowed
to warm to 25 °C and was then diluted with ether (3 mL). The layers were separated and
the aqueous layer was extracted with ether (2 mL). The combined organic solutions were
washed with saturated, aqueous sodium bicarbonate, dried (K2CO3) and concentrated in
71
vacuo. Chromatography of the residue (5% Et2OZhexanes with 0.1% Et3N, silica) afforded
a mixture containing two diastereomers in a ratio o f 2.2:1 as determined by GLC and
GCMS. The major product 113 was isolated as a colorless oil (70 mg, 63%). The minor
diastereomer (36 mg, 32%) proved to be very unstable and was not characterized.
NM R (C6D6, 300 MHz) 5 5.35 (1H, app s), 4.89 (1H, s), 4.84 (1H, s), 4.78 (1H, s), 4.76
(1H, s), 2.56 (1H, d, J = 13.5 Hz), 2.47-2.38 (1H, m), 2.32-2.24 (2H, m), 2.07-1.96 (3H,
m), 1.88 (3H, d, J = 1.8 Hz), 1.72 (3H, s), 1.68 (1H, d, J = 13.2 Hz), 1.49 (1H, s), 1.44
(1H, app t, J = 12.6 Hz), 0.12 (9H, s); 13C NMR (C6D6, 75 MHz) 5 149.2 (Q , 145.1
(Q , 139.8 (Q , 123.2 (OH), 112.2 ( 0 % ) , 109.7 (OH]), 74.1 (O), 46.0 (CH ]), 41.0 (OH]),
40.4 (OH), 31.5 (CH2), 28.9 (OH]), 20.7 (OH3), 17 .6 (0 % ), -1.0 (OH3); FTIR (neat)
3447, 2952, 1427, 1039, 849 cm"1; HRMS (PCI/CH4) calcd for C n ^ o O S i (M+H)+
279.2144, found 279.2126.
(±)-3-M ethyl-1-[(2-trimethy lsily lmethy l)-prop-1-enyl]cyclohex-2-en-1-ol, 115.
A 10 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon, charged with THF (2.5 mL) and cooled to -78
°C. A solution of M-BuLi (24 pL, 0.50 mmol, 2.11 M in hexanes) was then added via
syringe and the solution was stirred at -78 °C for 2 min. The allyl selenide 92 (111 mg,
0.50 mmol) was then added dropwise via syringe and the solution was stirred for 30 min
at -78 °C. A second 10 mL flask was flame dried under a stream o f argon was equipped
with a magnetic stirring bar and septum. A solution o f 3-methylcyclohex-2-en-1-one 114
(57 pL, 0.50 mmol) in THF (2.5 mL) was then added and the solution was cooled to -78
72
°C. The solution in the first flask was then transferred via cannula into the second flask
containing the cyclohexeneone solution.
The reaction mixture was quenched after
stirring for 15 min at -78 °C with a solution o f EtgNH+'CHgCO]" (0.8 mL, I M in THF).
The reaction mixture was allowed to warm to 25 °C and was then diluted with ether (3
mL). The layers were separated and the aqueous layer was extracted with ether (2 mL).
The combined organic solutions were washed with saturated, aqueous sodium
bicarbonate, dried (K2CO3) and concentrated in vacuo. Chromatography o f the residue
(5% Et2OZhexanes with 0.1% Et3N, silica) afforded the alcohol 115 as a colorless oil (1 10
mg, 92%). 1H NMR (C6D6, 300 MHz) 5 5.51 (1H, app s), 4.85 (2H, app s) 2.38 (1H, d,
J = 13.2 Hz), 2.33 (1H, d, J = 13.2 Hz), 1.92 (1H, d, J = 13.2 Hz), 1.87 (1H, d, J = 13.2
Hz), 1.80-1.67 (5H, m), 1.60 (3H, s), 1.58-1.54 (1H, m), 1.52 (1H, app s) 0.13 (9H, s);
13c NM R (C6D6, 75 MHz) 6 145.0 (Q , 136.3 (Q , 129.0 (OH), 111.9 ( 0 % ) , 70.2 (Q ,
50.9 (CH2), 36.2 (CH2), 30.6 (CH2), 28.9 (CH2), 23.9 (CH3), 20.0 (CH2), -1.0 (CH3);
FTIR (neat) 3447, 3071, 2934, 2829, 1670, 1627, 1438, 1247, 849 cm"1. HRMS (EI)
calcd for C i4 H 260S i (M-H2O)+ 220.1647, found 220.1641.
(±)-N-Methyl-4-phenyl-2-(trimethylsilylmethyl)-but-1-enamine, 117.
A 10 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream of argon, charged with THF (2.5 mL) and cooled to -78
°C. A solution o f H-BuLi (24 pL, 0.50 mmol, 2.11 M in hexanes) was then added via
syringe and the solution was stirred at -78 °C for 2 min. The allyl selenide 92 (111 mg.
73
0.50 mmol) was then added dropwise via syringe and the solution was stirred for 30 min
at -78 °C. A second 10 mL flame dried flask was equipped with a magnetic stirring bar,
septum and purged with argon. A solution o f N-benzylidine methyl amine 116 (62 pL,
0.50 mmol) in THF (2.5 mL) was then added and the solution was cooled to -78 °C. The
solution in the first flask was then transferred via cannula into the second flask containing
the immine solution. The reaction mixture was quenched after stirring for 15 min at -78
°C with a solution o f EtgNH+eCHgCC^ (0.8 mL, I M in THF). The reaction mixture
was allowed to warm to 25 °C and was then diluted with ether (3 mL). The layers were
separated and the aqueous layer was extracted with ether (2 mL). The combined organic
solutions were washed with saturated, aqueous sodium bicarbonate, dried (K jCO g) and
concentrated in vacuo. Chromatography o f the residue (5% Et2OZhexanes with 0.1%
Et3N, silica) afforded amine 117 as a colorless oil (111 mg, 90%). ^H NM R (C^Dg, 300
MHz) 5 7.52 (2H, d, J = 7.5 Hz), 7.30 (2H, dd, J = 7.8, 5.1 Hz), 7.19 (1H, d, J = 5.1 Hz),
4.83 (1H, app s), 4.73 (1H, app s), 3.72 (1H, dd, J = 5.4, 3.3 Hz), 2.40-2.36 (2H, m), 2.28
(3H, s), 1.56 (2H, s), 1.39 (1H, br s), 0.07 (9H, s); 13C NMR (C6D6, 75 MHz) 5 145.3
(O), 128.8 (CH), 127.9 (CH), 127.7 (OH), 127.4 (OH), 110.6 ( 0 % ) , 63.7, (OH), 48.9
(CH2), 35.1 (CHg), 26.6 (OH2), -L I (CHg); FTIR (neat) 3344, 3070, 3027, 2952, 2847,
2361, 2342, 1629, 1444, 1249, 840 cm"1. HRMS (PCIZCHq) calcd for C igH zsN Si
(M+H)+ 246.1688, found 246.1674.
(±)-N-Methylphenyl-2((trimethylsilyl)methyl)-4(2-methylethyl)-but-l-enamine, 119.
74
A 10 mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon, charged with THF (2.5 mL) and cooled to -78
°C. A solution o f M-BuLi (24 pL, 0.50 mmol, 2.11 M in hexanes) was then added via
syringe and the solution was stirred at -78 °C for 2 min. The allyl selenide 92 (111 mg,
0.50 mmol) was then added dropwise via syringe and the solution was stirred for 30 min
at -78 °C. A second 10 mL flame dried flask was equipped with a magnetic stirring bar,
septum and purged with argon. A solution o f N-(2-methylpropylidine)-benzilamine 118
(81 mg, 0.50 mmol) in THF (2.5 mL) was then added and the solution was cooled to -78
°C. The solution in the first flask was then transferred via cannula into the second flask
containing the cyclohexene oxide solution. The reaction mixture was quenched after
stirring for 15 min at -78 0C with a solution o f EtgNH+eCHgC 02 (0.8 mL, I M in THF).
The reaction mixture was allowed to warm to 25 °C and was then diluted with ether (3
mL). The layers were separated and the aqueous layer was extracted with ether (2 mL).
The combined organic solutions were washed with saturated, aqueous sodium
bicarbonate, dried (K2COg) and concentrated in vacuo. Chromatography o f the residue
(5% Et2OZhexanes with 0.1% Et3N, silica) afforded amine 119 as a colorless oil (125 mg,
87%). 1H NM R (C6D6, 300 MHz) 5 7.42 (2H, d, J = 7.5 Hz), 7.27 (2H, t, J = 6.9 Hz),
7.17 (1H, t, J = 7.2 Hz), 4.77 (1H, app s), 4.70 (1H, app s), 3.84 (1H, d, J = 13.2), 3.73
(1H, d, J = 13.2), 2.66 (1H, ddd, J = 17.1, 8.7, 3.9), 2.16-2.04 (2 H, m), 2.02-1.92 (1H,
m), 1.55 (2H, s), 1.25 (1H, s), 1.07 (3H, d, J = 6.9 Hz), 0.97 (3H, d, J = 6.9 Hz), 0.09
(9H, s); 13C NM R (C6D6, 75 MHz) 5 146.0 (Q , 142.1 (C) 127.2 (CE), 110.3 (CH2),
60.3 (CH), 52.8 (CH2), 39.7 (CH2), 30.0 (CE), 26.5 (CH2), 18.7 (CHg), 17.8 (CHg), -1.1
(CHg); FTIR (neat) 3324, 3067, 3027, 2955, 1629, 1464, 1457, 1249, 843 cm"1; HRMS
(PCI/CH4) calcd for C igH giN S i (M+H)+ 290.2304, found 290.2299.
75
Oxovanadium mediated cyclizations
Preparation o f dichloro(2,2,2-trifluoroethoxy)oxovanadium, 133.66
A 250 mL round bottomed flask equipped with a reflux condenser, magnetic
stirring bar and septum was flamed under a stream o f argon. 120 mL o f hexane was then
added followed by vanadium oxide trichloride (9.42 ml, 0.1 mol).
The solution was
stirred at 23 °C while 2,2,2-trifluoroethanol (7.28 mL, 0.1 mol) was added dropwise via
syringe with a constant flow o f argon to remove HCl evolved from the reaction. Upon
completion o f the addition the mixture was heated to reflux for 60 min. then allowed to
cool to 23 °C. The reflux condenser was then quickly replaced with a distillation head
which had previously been flamed under a stream o f argon.
The solvent was then
removed and the organometallic distilled at atmospheric pressure to give Dichloro(2,2,2trifluoroethoxy)oxovanadium (V) 133 as a light yellow liquid (19.4 g, 82%, BP 135-140
°C). 1H NMR (C6D6, 300 MHz) 6 4.4 (br s); 13C NMR (C6D6, 75 MHz) 5 127.7 (d, J =
925 Hz), 84.1-83.2 (m); 51V NMR (C6D6, 250 MHz) 5 -281.6 (s) from 51VOCl3.
General procedure for 1,4-additions.
Preparation of I -((trimethylsilyl)oxy)-3-(2-
(trimethylsilylmethyl)prop-1-enyl)cyclopent-1-ene, 128.
OTMS
TMS
76
Al OO mL round bottomed flask equipped with a magnetic stirring bar and septum
was flame dried under a stream o f argon. THF (4 mL) was added and cooled to -7 8 °C.
n-BuLi (2.45 mL, 6.0 mmol, 2.45 M) was then added followed by the dropwise addition
o f 2-(trimethylsilylmethyl)-2-methylselenoprop-1-ene 92 (1.26 mL, 6.0 mmol).
This
solution was allowed to stir at -7 8 °C for 30 min. A second 50 mL round bottomed flask
equipped with a magnetic stirring bar and septum was flame dried under a stream o f
argon followed by the addition CuI (1.143 g, 6.0 mmol). The flask was agian purged
with argon and then TMEDA (2.71 mL, 18.0 mmol) was added. To this slurry was added
THF (25 mL) and the solution was stirred at room temperature until hogeneous. The
C uI TMEDA solution was then transferred via cannula into the first flask containing the
ally I lithiate with THF wash (2.5 mL). This solution was then stirred at -7 8 0C for 6
min., placed in an ice-water bath for 6 min. and again cooled to -7 8 0C. After stirring at
-7 8 °C for 6 min. TMSCl (1.91 mL, 15 mmol) was added in one portion via syringe
followed immediately by the addition o f cyclopent-2-en-1-one 25 (0.502 mL, 6.0 mmol)
via syringe. The reaction mixture was then stirred for 30 min. at -7 8 °C and poured in to
a separatory funnel containing 0.1 M HCl (30 mL) and pentane. The layers were mixed
slightly, separated and the aqueous layer was extracted with pentane (2 x 20 mL). The
combined organic extracts were washed with saturated aqueous NaHCO3, dried (anhy.
N a2SO4) and filtered through a pad o f celite. The solvent was then removed in vacou and
the residue added to DMSO (5 mL).
The DMSO mixture was then extracted with
pentane (3 x 25 mL). The combined organic phases were washed with saturated aqueous
NaHCO3, dried (anhy. Na2SO4), filtered, concentrated and placed under high vacuum (10.5 mmHg) for 30 min. (to remove the butyl methyl selenium byproduct) to afford crude
the silyl enol ether as a colorless oil in a high state o f purity as determined by 1H NMR.
The silyl enol ether was used immediately in the next reaction.
77
General procedure for oxovanadium induced cyclizations. Preparation o f hexahydro-5methylene-1 -(2H)-pentalenone, 131.
O
A 100 mL round bottomed flask equipped with a magnetic stirring bar and septum
was
flame
dried
under a stream o f argon,
charged with
CH2Cl2 (40 mL),
VO(OCH2CF3)Cl2 (1.95 mL, 12 mmol) and cooled to -7 8 0C. The silyl enol ether 128
prepared above was dissolved in CH2Cl2 (5 mL) was then added via syringe pump over
60 min. The reaction mixture was stirred another 10 min. at -7 8 0C and poured into a
seperatory funnel containing 1.5 M HCl (10 mL) and ether (30 mL). The layers were
mixed, separated and the aqueous layer extracted with ether (2 x 20 mL). The combined
organic extracts were washed with saturated aqueous NaHCO3, dried (MgSO4), and
concentrated.
Chromatography of the residue (2.5% Et2OZpentane with 0.01% Et3N,
silica) gave bicyclic ketone, 131, as a colorless oil (0.669 g, 82%). Spectral data were
consistent with that reported in the literature.67 1H NMR (C6D6, 300 MHz) 8 4.85 (app s,
1H), 4.82 (app s, 1H), 2.57 (d, 1H, J = 18.3 Hz), 2.46-2.36 (m, 1H), 2.27-2.22 (m, 3H),
2.01-1.88 (m, 2H), 1.84-1.73 (m, 1H), 1.53 (m, 1H), 1.20 (ddd, 1H, J = 15.9, 8.7, 3.9);
13C NM R (C6D6, 75 MHz) 5 150.9 (C), 107.0 (CH2), 51.8 (CH), 40.7 (CH), 39.4 (CH2),
37.1 (CH2), 35.3 (CH2), 26.2 (CH2).
78
Preparation o f I -((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop-1-enyl)cyclohex-1ene 129, and c/-$'-hexahydro-2-methylene-4H-inden-4-one, 132.
OTMS
O
Cyclohex-2-en-l-one was subjected to the series of reaction conditions described
above for conjugate addition and cyclization.
The residue after work-up and
concentration was purified by flash chromatography (2.5% Et2OZpentane with 0.01%
Et3N, silica) to give the bicyclic ketone, 132, as a colorless oil (0.702 g, 78%). Spectral
data were consistent with that reported in the literature.67 1H NMR (C6D6, 300 MHz) 5
4.99 (m, 2H), 2.91 (ddd, IH 5J = 6.5, 5.7, 2.1 Hz), 2.46-2.39 (m, 1H), 2.27-2.15 (m, 1H),
2.13-1.88 (m, 5H), 1.47 (ddd, I H J = 17.7, 9.0, 5.4 Hz), 1.39-1.27 (m, 2H), 1.15 (ddd,
IH 5J = 16.2, 6.0, 1.8 Hz); 13C NMR (C6D6, 75 MHz) 5 209.9 (C), 107.2 (CH2)5 52.9
(CH), 42.8 (CH), 39.7 (CH2)538.1 (CH2)533.4 (CH2)526.6 (CH2) 23.8 (CH2).
Preparation
of
2-methyl-1-((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop-1-
enyl)cyclopent-1-ene, 135, and hexahydro-5-methylene-6a-methyl-l-(2H)-pentalenone,
2-methylcyclopent-2-en-1-one, 134, was subjected to the series o f reaction
conditions described above for conjugate addition and cyclization.
The residue after
work-up and concentration was purified by flash chromatography (2.5% Et2OZpentane
with 0.01% Et3N 5 silica) to give the bicyclic ketone, 139, as a colorless oil (0.639 g,
79
71%). 1H NMR (C6D6, 300 MHz) 5 4.88 (app s, 1H), 4.84 (app s, 1H), 2.52 (d, 1H, J =
16.8 Hz), 2.47-2.38 (m, 1H), 2.13-1.86 (m, 4H), 1.63-1.51 (m, 1H), 1.36-1.27 (m, 1H),
1.22-1.12 (m, 1H), 1.00 (s, 3H);
NMR (C6D6, 75 MHz) 5 150.4 (C) 107.5 (CH2),
56.3 (C), 48.1 (CH), 42.7 (CH2), 38.9 (CH2), 36.6 (CH2), 25.2 (CH2), 21.6 (CH3); FTIR
(neat) 2928, 1739, 1647, 1406,1065 c m 1; HRMS (EI) calcd. for C 10H 14O (M+) 150.1045,
found 150.1039.
Preparation
of
2-methyl-5-/?-(2-methylethenyl)-l-((trimethylsilyl)oxy)-3-/?-(2-
(trimethylsilylmethyl)prop-1-enyl)cyclohex-1-ene, 136, and cN-Hexahydro-3a-methyl-2methylene-6-/?-((2-methyl)prop-1-enyl)-4//-inden-4-one, 140.
(R)-Carvone, 112, was subjected to the series of reaction conditions described
above for conjugate addition and cyclization.
The residue after work-up and
concentration was purified by flash chromatography (2.5% Et2OZpentane with 0.01%
Et3N, silica) to give the bicyclic ketone, 140, as a colorless oil (1.016 g, 83%). ^H NMR
(C6D6, 300 MHz) 6 5.04 (m, 1H), 4.98 (m, 1H), 4.78 (m, 1H), 4.71 (m, 1H), 3.50 (d, 1H,
J=
15 Hz), 2.36-2.32 (m, 3H), 2.18-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.97-1.91 (m,
1H)1.90-1.88 (m, 1H), 1.60-1.48 (m ,lH), 1.54 (s, 3H), 1.03 (s, 3H); 1^C NMR (C6D6, 75
MHz) 5 211.7 (C), 148.9 (C), 147.7 (C), 110.4 (CH2), 106.9 (CH2), 54.7 (C), 47.2 (CH),
43.0 (CH2), 42.4 (CH2), 41.1 (CH), 37.2 (CH2), 29.6 (CH2), 23.6 (CH3), 20.9 (CH3)D
FTIR (neat) 2927, 1709, 1644, 1446, 1377, 1248 c m 1; HRMS (EI) calcd. for C 14H20O
(M+) 204.1514, found 204.1507.
80
Preparation o f Trimethyl [(4-(2-(trimethylsiIylmethyl)prop-1-enyl)-4H-1-benzopyran-2yl)oxy] silane,
138,
and
cis-2,
3,
3a,
9b-tetrahydro-2-methylene-
cyclopenta[c] [ I ]benzopyran-4//-( I )-one, 141.
Coumarin, 137,was subjected to the series o f reaction conditions described above
for conjugate addition and cyclization. The residue after work-up and concentration was
purified by flash chromatography (2.5% Et2OZpentane with 0.01% Et3N, silica) to give
hydrindan, 142, as a white solid. (0.876 g, 73%). Spectral data were consistent with that
reported in the literature.67 1H NMR (C6D6, 300 MHz) 5 7.22-7.01 (m, 4H), 4.96-4.93
(m, 2H), 3.43 (dt, IH, J = 9.3, 7.2 Hz), 3.15 (ddd, 1H, J = 7.5, 3.9, 0.9 Hz), 3.04 (br d,
1H, J = 16.5 Hz), 2.82-2.69 (m, 2H), 2.42 (ddd, 1H, J = 14.4, 9.6, 1.8 Hz); 13C NMR
(C6D6, 300 MHz) 5 170.2 (C), 151.3 (C), 146.8 (C), 128.9 (CH), 128.6 (CH), 125.0 (CH),
124.0 (C), 117.4 (CH), 108.4 (CH2), 43.2 (CH), 40.8 (CH), 40.4 (CH2), 35.5 (CH2).
Oxidative homo-coupling of silyl enol ethers
General procedure
A 100 mL round-bottomed flask equipped with a magnetic stirring bar and
septum was flame dried under a stream o f argon. The flask was then charged with
methylene chloride (25 mL) and cooled to -78 °C. VO(OTFE)Cl2 (12 mmol) was then
81
added via syringe. A solution o f the silyl enol ether 162 (6 mmol) in methylene chloride
(4 mL) was then added via syringe with the aid o f a syringe pump over 30 min. Upon
complete addition o f the silyl enol ether solution the reaction mixture was poured into a
separatory funnel containing an aqueous solution o f HCl (5 mL, 5%) and ether (20 mL).
The layers were mixed, separated and the aqueous layer was washed with ether ( 5mL).
The combined organic solutions were then washed with saturated aqueous sodium
bicarbonate (10 mL), brine (10 mL), dried (MgSOq.), filtered and concentrated.
The
residue was then purified by flash chromatography (5% ethyl acetate/hexanes, silica) to
give 165 as a white solid.
Spectral data were consistent with that reported in the
literature.66 1H NM R (CDCl3, 300 MHz) 5 2.87-2.82 (m), 2.63-2.59 (m), 2.42-2.39 (m),
2.37-2.32 (m), 2.29-2.18 (m), 2.09-1.91 (m), 1.88-1.82 (m), 1.75-1.52 (m), 1.35-1.23 (m);
13C N M R (CDCl3, 75 MHz) 5 211.6 (C), 210.6 (C), 50.2 (CH), 48.9 (CH), 42.2 (CH2),
41.7 (CH2), 30.0 (CH2), 29.0 (CH2), 28.0 (CH2), 26.4 (CH2), 25.4 (CH2), 24.9 (CH2).
Oxidative cross-coupling o f silyl enol ethers
General procedure
A 100 mL round-bottomed flask equipped with a magnetic stirring bar and
septum was flame dried under a stream o f argon.
The flask was then charged with
methylene chloride (25 mL) and cooled to -78 °C. VO(OTFE)Cl2 (12 mmol) was then
added via syringe. A mixture of the silyl enol ethers 163 (6 mmol) and 168 (6 mmol) in
methylene chloride (4 mL) was then added via syringe with the aid o f a syringe pump
over 30 min. Upon complete addition the reaction mixture was poured into a seperatory
funnel containing an aqueous solution o f HCl (5mL, 5%) and ether (20 mL). The layers
were mixed and separated. The organic solution was then washed with saturated aqueous
sodium bicarbonate (10 mL), brine (10 mL), dried (M gS04), filtered and concentrated in
82
vacuo.
The residue was then purified by flash chromatography
(5%
ethyl
acetate/hexanes, silica) to give 168 as a white solid. Spectral data were consistent with
that reported in the literature.66 The ratios o f homo and cross coupled products were then
determined by GLC and GCMS. 1H NMR (CDCl3, 300 MHz) 5 2.98-2.84 (m), 2.30-2.25
(m), 2.15-2.08 (m) 2.04-1.92 (m), 1.79-1.48 (m), 1.32-1.18 (m), 1.06 (s).
13C NM R
(CDCl3, 75 MHz) 5 214.7 (C), 212.0 (C), 46,5 (CH), 44.4 (C), 42.3 (CH2), 37.0 (CH2),
34.4 (CH2), 28.3 (CH2), 26.9 (CH3), 25.7 (CH2).
83
REFERENCES
1 Mitra, A. “The Synthesis o f Prostaglandins” Wiley: New York, 1977.
2 (a) Comer, F. W.; McCapra, F.; Trotter, J.; Scott, A. I. Chem. Comm. 1965, 310. (b)
Comer, F. W.; Trotter, J. J. Chem. Soc. B 1966, 11. (c) Comer, F. W.; McCapra, F.;
Qureshi, I. H.; Scott, A. I. Tetrahedron, 1967, 23, 4761.
3 Hudlicky1T .; Sinai-Zingde, G.; Natchus, M. G.; Ranu, B. C.; Papadopolous, P.
Tetrahedron, 1987, 43, 5685.
4 Reviews o f the Nazarov cyclization: (a) Habermas, K. L.;Denmark, S. E.; Jones, T. K.
In Organic Reactions', Paquette, L. A., Ed.; John Wiley & Sons: New York, 1994; Vol.
45, pp 1-158. (b) Denmark, S. E. In Comprehensive Organic Synthesis', Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp. 751-784.
5 Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1 9 8 2 ,104, 2642.
6 Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T. J. Org. Chem. 1995, 60, 2320.
7 Pagenkopf, B. L.; Livinghouse, T. J. Am. Chem. Soc. 1996,118, 2285.
8 Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1 996,1 1 8 ,11672.
9 Murakami, M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1 9 9 7 ,119, 2950.
10 Rieke, R. D.; Sell, M. S.; Xiong, H. J. Am. Chem. Soc. 1995,117, 5429.
11 Danheiser, R. L.; Carini, D. J.; Basak, A. J. Am. Chem. Soc. 1 9 8 1 ,103, 1604.
12Binger, P.; Such, M. Top. Curr. Chem. 1 9 8 7 ,135, 77 and references therein.
13 Bates, R. B.; Beavers, W. A.; Gordon, B.; Mills, N. S. J. Org. Chem. 1979, 44, 3800.
14 (a) Little, R. D. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Ed.;
Pergamon Press, Ltd. New York, 1993; Vol. 5, p 239. (b) Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1986, 25, I. and references therein, (c) Trost, B. M. Pure App. Chem. 1988,
60, 1615 and references therein.
15 Majetich, G.; Nishidie, H.; Zhang, Y. J. Chem. Soc., Perkin Trans. 1 , 1995,453.
16 Bardot, V.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J, -C. Synlett. 1996, 37.
84
17 (a) Fleming, I.; Barbero, A. Chem. Rev. 1997, 97, 2063. (b) Langkopf, E.; Schinzer, D.
Chem. Rev. 1995, 95, 1375.
18 Hosomi, A.; Sakurai, H. J Am. Chem. Soc. 1977, 99, 1673 (b) Sakurai, H.; Hosomi,
A.; Hayashi, J. Org. Synth. 1984, 62, 86.
19 Kercher, T.; Livinghouse, T. J. Am. Chem. Soc. 1 9 9 6 ,1 18,4200.
20 Kercher, T. Doctoral Thesis, Montana State University, 1997.
21 Miginiac, L.; Guyot, B.; Pomet, J. Tetrahedron 1991, 47, 3981.
22 Santelli, M.; Pons, J. Lewis Acids and Selectivity in Organic Synthesis CRC Press, Inc.,
N ew York; 1996; p 231 and references therein.
23 Pan, L. -R .; Tokoroyama, T. Tetrahedron Lett. 1992, 3 3 ,1496.
24 Knapp, S.; 0 ”Connor, U.; Mobilio, D. Tetrahedron Lett. 1980, 21, 4557.
25 Monteiro, H. J.; De Souza, I. P. Tetrahedron Lett. 1975,11, 921.
26 Monteiro, H, J., Gemal, A. L. Synthesis, 1975, 437.
27 Kato, M.; Ouchi, A.; Yoshikoshi, A. Chem. Lett. 1983,1511.
28 Hulce, M.; Mallamo, J. P.; Frye, L. L.; Kogan, T. P.; Posner, G. H. Org. Syn. 1985, 64,
196.
29 Smith, A. B.; Branca, S. J.; Guaciaro, M. A.; Wovkulich, P. M.; Kom, A. Org. Syn.
1982, 61, 65.
30 Posner, G. H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.; Cun-heng, H.; Clardy, J.
Tetrahedron 1986, 42, 2919 and references therin.
31 Seyferth, D.; Wiener, M. A. J. Org. Chem. 1961, 26, 4797 and references therein.
32 Hiiro, T.; Kambe, N.; Ogawa, A.; Miyoshi, N.; Murai, S.; Sonoda, N. Angew. Chem.
Int. E d, Engl. 1987, 26, 1187.
33 (a)Kang, K. - t ; U, J. S.; Kim, I. K.; Kim, W. J. Bull. Korean Chem. Soc. 1 9 9 5 ,16,
464. (b) Kang, K, -T.; Sung, T. M., Kim, J. K.; Kwon, Y. M. Syn. Comm. 1997, 27,1173.
34 Clarembeau, M.; Krief, A. Tetrahedron Lett. 1984, 25, 3629.
85
35 Trost, B. M.; Vincent, J. E. J. Am. Chem. Soc. 1 9 8 0 ,102, 5680.
36 Ryter, K.; Livinghouse, T. J. Org. Chem. 1997, 62, 4842.
.
37 Hirao, T. Chem. Rev. 1997, 97, 2707 and references therein.
38 Bergdahl, M.; Eriksson, M.; Nilsson, M.; Olsson, T. J. Org. Chem. 1993, 58, 7238.
39 For an extensive review see Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 4 1 ,135
40 Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Smith, R. A. J. Org. Chem. 1989, 54,
4977.
41 Bertz, S. H.; Eriksson, M.; Maio, G.; Snyder, J. P. J. Am. Chem. Soc. 1 9 9 6 ,118, 10906.
42 (a) Bertz, S. H.; Miao, G.; Rossiter, B. E.; Snyder, J. P. J. Am. Chem. Soc. 1995,117,
11023 and references therein.
43 Johnson, C. R.; Marren, T. J. Tetrahedron Lett. 1987, 2 8 ,27.
44 (a) Hirao, T.; Mori, M.; Ohshiro, Y. Bull. Chem. Soc. Jpn. 1989, 62, 2399.
45 (a) Hirao, T.; Fujii, T.; Ohshiro, Tetrahedron 1994, 5 0 ,10207. (b) See also Noyori, R.;
Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899.
46 Ryter, K.; Livinghouse, T. J. Am. Chem. Soc. 1 9 9 8 ,120, 2658.
47 (a) Lipschutz, B. H.; Parker, D. A.; Kozlowski, J. A.; Nguyen, S. L. J. Org. Chem.
1984, 25, 5959. (b) Yamamoto, Y. Angew. Chem. Int. Ed., Engl. 1986, 25, 947 and
references therein.
48 Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1995, 68, 322.
49 Fujii, T.;Hirao, T.; Ohshiro, Y. Tetrahedron Lett. 1992, 33, 5823.
50 Seto, H.; Sas aka, T.; Takeuchi, S.; Yonehara, H. Tetrahedron Lett. 1978, 4411.
51 Paquette, L. A.; Annis, G. D. J. Am. Chem. Soc. 1983,105, 7358. "
52 Takahashi, S.; Takeuchi, M.; Arai, M.; Seto, H.; Otake, N. J. Antibiot. 1983, 3 6 ,226.
53 Kercher, T.; Livinghouse, T. J. Am. Chem. Soc. 1 9 9 6 ,1 1 8 ,4200.
86
54 Luche, J. -L .; Damiano, J. - C . J. Am. Chem. Soc. 1980,102, 7926
55 For a similar transformation see Ihara, M.; Katogi, M.; Fukumoto, K. J. Chem. Soc.
Perkin Trans. 1 , 1988, 2963 and references therein.
56 Fox, M. A.; Cardona, R.; Ranade, A. C. J. Org. Chem. 1985, 50, 5016 and references
therin.
57 Crimmins, M. T.; Deloach, J. A. J. Am. Chem. Soc. 1986,108, 800.
58 Pilcher, A. S.; D eshong,, P. J. Org. Chem. 1996, 61, 6901.
59 Majetich, G.; Hull, K.; Casares, A. M.; Khetani, V. J. Org. Chem. 1991, 56, 3958.
60 Kauffman, G. B.; Fang, L. Y. Inorg. Syn. 1983, 2 2 ,101.
61 Molander, G. A.; Schubert, D. C. Tet. Lett. 1986, 27(7), 787-790 and references there­
in.
62 Walshe, N. D. A.; Goodwin, G. B. T.; Smith, G. C.; Woodward, F. E. Org. Syn. 1987,
65, I .
63 Box, V. G. S.; Brown, D. P. Heter. 1991, 32(7), 1273-1277.
64 The stereochemical assignment for alcohols 13a and 13b was based on the observed
IR chemical shift o f the hydroxyl (C-OH) resonance in DMSO-Jd in analogy with the
corresponding resonance in cis-, trans-1-R-4-t-butylcyclohexan-1-ol (R = Me, 6 3.56
and 4.15 respectively). For alcohols 13a and 13b the hydroxyl (C-OH) resonance was
observed at (DMSO-Jg) 6 3.29 and 3.94 respectively. Meakins, G. D.; Percy, R. K.;
Richards, E. E.; Young, R. N. J. Chem. Soc. C 1968,1106.
65 The stereochemistry of the ring opening was determined by comparison with cis-,
fr<ms-2-methylcyclohexan-1-ol in which the a-proton (CJT-OH) o f the hydroxyl group
adsorbs at 5 3.63-3.97 and 2.75-3.40 respectively: Iguchi, S.; Nakai, H.; Hayashi, M.;
Yamamoto, H.; Maruoka, K. Bull. Chem. Soc. Jpn. 1981, 54, 3033-3041.
66 Hirao, T.; Mori, M.; Ohshiro, Y. Bull. Chem. Soc. Jpn. 1989, 62, 2399-2400.
67 Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1 9 8 3 ,105, 2315-2325.
68 Kauffman, G. B.; Fang, L. Y. Inorg. Syn. 1983, 22, 101-103.
69 Hirao, T.; Mori, M.; Ohshiro, Y. Bull. Chem. Soc. Jpn. 1989, 62, 2399-2400.
87
APPENDIX
88
cz>Hexahydro-5-methylene-6a-(j9-touenelthio)-1(2/^)-pentalen-1-one, 69.
1H NMR (CDCl3, 300 MHz)
INTEGRAL
PPM
V . L T G P 7
7 .2 3 ^ :1 4
7 . 1 1111
7.^4.L4
__
C G9-
r,iesii
4 . P434r
Q 4sr
2.7SP1
89
c/.s-Hexahydro-5-methylene-6a-(/>-touenelthio)-1(2//)-pentalen-1-one, 69.
13C NMR (CDCl3, 75 MHz)
PPM
1 4 7 . /SC
W fM W k '
13^ . QB-i
12 9 6 3 3
107 , Zt!?
oC
3)
OJ
77.427
77 , OCc76 S S
46
41 . /)21
26 2 c 2
?.= r b 9 S
ro.
o
c -
22 . 6 9 2
21 . 2 0 5
90
cw-Hexahydro-5-methylene-6a-0-touenelthio)-1(2//)-pentalen-1-one, 69.
DEPT NMR (CDCl3, 135° pulse)
PPM
J
147.7°?
61
J
129 b?.~
i
Wdu
107.;:°
<
76 : e i
46 n - f :
41.,
I
,692
I
91
c/s-Hexahydro-2-methylene-3a-(/>toluenethio)-4//-inden-4-one, 70.
1H NMR (CDCl3, 300 MHz)
I
TNTGf i AL
PPM
7T45PP
7. .TC.-;
7 , , o 4 14
4.£.?:?r
a
. C - .
^ jI
-n"]
5 -j I l f i h
:: ;
~
- 7 i IF
_
: _43.
■■ .. 4 0 £ Q
G4L
L --T..:
= S jS /7 =3 I
L . T: c T- 7 °
- 46129
Z. 4:2%3
g . 4EG3L . 40 7 I 7
£.z3n74
-H m
■r..
O
5793
12£5
92
czs-Hexahydro-2-methylene-3a-(p-toluenethio)-4//-inden-4-one, 70.
13C NM R (CDCl3, 75 MHz)
CDM
146 4 4 6
i: - 6
»34
129.694
107.rs r
PPM
77.421
75 TDD
=T
48 f / ?
42 PGP
^7
19°
24
17^
,glp
93
c/5-Hexahydro-2-methylene-3a-(/7-toluenethio)-4//-inden-4-one, 70.
DEPT NMR (CDCl3, 135° pulse)
OOk-
I hI U
ItiO
140
i ? r. . j g p
I'..1 hQ
•:7 rt:
4- :. ~
a
:. .
r 7 .
,V
17 i
. I. A
94
2-(Trimethylsilylmethyl)-2-methylselenoprop-1-ene, 92.
H NM R (CDCl3, 300 MHz)
O
o
1.871
— 1 .663
-----1 . 6 6 0
95
2-(Trimethylsilylmethyl)-2-methylselenoprop-1-ene, 92.
13C NMR (C6D6, 75 MHz)
DEPT NMR (C6D6, 135° pulse)
Si(CH3)3
------------ 1 1 0 . 6 1 5
------------ 3 3 . 6 2 9
------------ 2 5. 1 3Z
■4 4
- -0.97:
96
2-(Trimethylsilylmethyl)-pentadodec-1-ene, 105.
1H NMR (CDCl3, 300 MHz)
-4.535
-4 .5 5 1
______ _ 516
■— 1 . 5 0 1
— ------ 1 . 3 9 6
*— 1 . 3 7 3
---------- 1 . 2 3 9
97
2-(Trimethylsilylmethyl)-pentadodec-1-ene, 105.
13C NMR (CDCl3, 75 MHz)
DEPT NMR (CDCl3, 135° pulse)
m
X
CZD
CD
<
X
3
CD
o_
CD
O-
O
O
O
03
CO -
(Z)
CD
X
W
o -
------------ - 0 . 8 9 9
98
C is-4-( I , I -dimethylethyl)-1-[(trimethylsilylmethyl)-prop-1-enyljcyclohexan-1-ol, 109a
1H NMR (CDCl3, 300 MHz)
m
X
B
nf
z
3
CO
O
<
CD
3
O
O
O
^
S - -
4.721
4 . 1 14
- 4 645
-4 .6 3 8
N) —
I
1.656
1.631
1.439
4
0.096
0.079
0.037
0.033
0.028
TJ
I
99
Cis-A-( I , I -dimethylethyl)-1-[(trimethylsilylmethyl)-prop-1-enyljcyclohexan-1-ol, 109a
13C NM R (CDCl3, 75 MHz)
DEPT NMR (CDCl3, 135° pulse)
NJ -
r
;
NJ
O
T3
I
:
100
Trans-A-{ I, I -dimethylethyl)-1-[(trimethylsilylmethyl)-prop-1-enyljcyclohexan-1-ol,
I
AM
109b
1H NMR (CDCl3, 300 MHz)
101
7>tim-4-( I . I -dimethylethyl)-1-[(trimethylsilylmethyl)-prop-1-enyl]cyclohexan-1-ol,
109b
13C NMR (CDCl3, 75 MHz)
DEPT NMR (CDCl3, 135° pulse)
144.777
111.507
77.827
77.406
76.982
70.492
MOq*
52.180
48.357
------------------
38.627
-----------------------------------
32.800
30.009
27.988
-----------------
23.041
------------------
-
1.047
102
(±)-rra«5-2-[2-(trimethylsilylmethyl)-prop-2-enyl]cyclohexan-l-ol, 111.
1HNMR (C6D6, 300 MHz)
:: :*•?:■?
:: s‘5
it;
. it:
I iS3
I 5‘ *
i
S-Jt
:
I . 185
—
——' "
:i ;;s«
5 409
—
4 462
132
.. OOOOOOOO
I . 135
103
(±)-7m«5-2-[2-(trimethylsilylmethyl)-prop-2-enyl]cyclohexan-1-ol, 111.
13C NMR (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
147.478
-C
128.512
128.192
127.872
109.330
75.223
43.684
43.004
I
36.244
31.080
26.768
26.096
25.380
104
5-(2-Methyl-1-ethenyl)-2-methyl-1-[((2-(trimethylsilyl)methyl)-prop-1-en]-cyclohex-2en-l-ol, 113.
I h n m r (CeDe, 3 0 0 m h z )
105
5-(2-Methyl-1-ethenyl)-2-methyl-1-[((2-(trimethylsilyl)methyl)-prop-1-en]-cyclohex-2en-l-ol, 113.
13c NMR (Cf)Dfr, 75 MHz)
m
"I
X
"D
-
OO
:
W
o
Z
33
OO-
O
o
128 500
1 : 8 180
127.859
123.1 55
112.18:
109 616
31 5 2 0 29 5 ' 3
20 735
«"*59:
-i.0 3 :
106
5-(2-Methyl-l-ethenyl)-2-methyl-l-[((2-(trimethylsilyl)methyl)-prop-l-en]-cyclohex-2en-l-ol, 113.
DEPT NMR (C6D6, 135° pulse)
K)
OO
OD -
O
a> o
—
o
to —
O
OO
CD
O
cr.
o
O
O-
U
107
(±)-3-Methyl-1-[(2-trimethylsilylmethyl)-prop-1-enyl]cyclohex-2-en-1-ol, 115.
lH NMR (C6D6, 300 MHz)
O
m
Ln
o
4 B5S
4 es:
Ln
o
w
Ln
w
o
N>
r-2.
Il
8? '
812
IC
6»S'
68*
66»
Ln
622
I 626
604
N 1. 681
^ I 565
o
O
Ln
-Z-O 143
13
13
3
108
(±)-3-M ethyl-1-[(2-trimethylsilylmethyl)-prop-1-enyl]cyclohex-2-en-1-ol, 115.
13C NM R (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
200
180
160
GJ
140
■ 136. 33-»
120
128 886
129
125 191
1 2 7 . 9'C
100
80
60
40
------------ 3 6 . 2 4 9
—— — 3 0 . 5 6 6
----------- 28 944
20
------------ 2 3 . 8 9 2
------- 199'?
0
ppm
109
(±)-N-Methyl-4-phenyl-2-(trimethylsilylmethyl)-but-1-enamine, 117.
IR NMR (C6D6, 300 MHz)
3 1«
3.726
3.715
3.697
I.=
2.449
2.403
2.38:
2.3"F
2.3H
2.36-’
.2.36«
2.283
I
N) —
_ ^ - 1.562
^^-1.560
U
■
I •394
0.080
0.076
0.072
0.066
0.033
n•o
3
no
(±)-N-Methyl-4-phenyl-2-(trimethylsilylmethyl)-but-1-enamine, 117.
13c NM R (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
_____ 1 4 5 . 4 0 3
------ 1 4 5 . 2 0 0
1 2 1 . I3B
121.5 14
121.193
127.1 72
127.743
127.3 64
------------ 1 1 0 . 1 1 3
111
(±)-N-Methylphenyl-2((trimethylsilyl)methyl)-4(2-methylethyl)-but-l-enamine, 119.
IR NMR (C6D6, 300 MHz)
O
3 . B6:
381 =
UJ
CJi
LU
2.611
2.655
2.642
2.621
2.16:
2.146
2.113
2 . IOC
2.086
2.056
2.042
2.024
O
NJ
CJl
NJ
O
S
CJI
O
O
CJI
I
I O'"1.056
1.026
0. 98C
0.95"
0.931
0.354
0.282
0.2H
0.219
0.159
ppm
112
(±)-N-Methylphenyl-2((trimethylsilyl)methyl)-4(2-methylethyl)-but-1-enamine, 119.
13c NM R (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
CD
-
------------ 1 4 6 . 0 0 1
------------ 1 4 2 . 0 7 1
121.3 13
126.1 92
127.6 72
127.1 36
N> -
110. 333
------------ 6 0 . 0 2 5
------------ 5 2 . 7 5 1
------------ 3 9 . 7 0 6
---- -------- 18 707
------------ 1 7 . 7 8 7
113
Dichloro(2,2,2-trifluoroethoxy)oxo vanadium, 133.
1H NMR (C6D6, 300 MHz)
OO-
(T . -
I ■000
0.040
0.046
0.016
O-
114
Dichloro(2,2,2-trifluoroethoxy)oxovanadium, 133.
13C NM R (C6D6, 75 MHz)
115
Dichloro(2,2,2-trifluoroethoxy)vanadium oxide, 133.
51VNMR (C6D6, 250 MHz)
VO(OTFE)C12
C6D6
250 MHz
CD
O
O-U
O -
O
cr.
o o
cn
o
O
O
O
LJ
i . OOC
I
O
KJ
O
O
O -
O
8 . 180 __ o -
i
O
O
0.193
I
M
O
O
S
I
LU
O
O
I
O
O
I
<_n
o
o
TJ
:
n ■
3i
116
I -((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop-1-enyl)cyclopent-1-ene, 128.
1H NMR (C6D6, 300 MHz)
W
O
rV
I
117
I -((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop-1-enyl)cyclopent-1-ene, 128.
13c NM R (C6D6, 75 MH z )
DEPT NMR (C6D6, 135° pulse)
200
180
160
140
128.500
129.1 90
12-».859
120
100
80
60
40
----------- 2 8 . 5 9 6
----------- 27 087
20
0
118
Hexahydro-5-methy Iene-1-(2H)-pentalenone, 131.
1H NMR (C6D6, 300 MHz)
7.226
4
4 332
4.826
4.821
0.540
0.518
0.548
0.522
"0 •
I
119
Hexahy dro-5-methylene-1-(2H)-pentalenone, 131.
13c NM R (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
C
r
N)
O
O
I
OO
O
O
r
150.944
O
128. 51
128.194
127.874
N) —
O
107.025
OO
:
00
O
<
OJ\
51.790
O
:
40.664
39.357
37.093
35.341
26.225
ro
o
o;
TJ
TJ
3
120
I -((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop-1-enyl)cyclohex-1-ene 129.
1H NMR (C6D6, 300 MHz)
YYTsY W
121
I -((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop- 1 -enyl)cyclohex- 1 -ene 1 2 9 .
13c NM R (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
CO -
m1 5 1. 313
1 4 6. 053
1 2 8. 513
1 2 8. 192
127.871
----------- 1 1 1 . 391
----------- 109.5 11
— 1 0 8. 399
4 6 .6 7 2
33.209
3 0. 74 9
30 .711
2 9 .7 5 2
2 6 .6 2 7
25.546
22.289
------------0 . 6 2 7
-------------- I .041
122
cw-Hexahy dro-2-methylene-4H-inden-4-one, 132.
1H NMR fCfiDfi, 300 MHz)
<
123
c/j-Hexahydro-2-methylene-4H-inden-4-one, 132.
13c NMR (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
2 0 9. 9 7 0
149
774
1 2 8 .5 1?
128.1 91
1 2 7. 870
1 2 7. 5 4 6
107. 231
52 .902
23.3?c----------- 26 € 7 '
----------- 23 84r
124
2-m ethyl-1-((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop-1-enyl)cyclopent-1-ene,
135.
I r NM R (C6D6, 300 MHz)
I -094^~
!.Hiy-
125
2-m ethyl-1-((trimethylsilyl)oxy)-3-(2-(trimethylsilylmethyl)prop-1-enyl)cyclopent-1-ene,
135.
13c NM R (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
OO
OD -
O
oO> —
O
-
116.119
108.950
OO
00
O
--- ---------—
O
________
--------------------------------------------
ND
O
O
I
43.821
43.346
32.960
32.556
26.983
23.312
13.881
10.794
___________
0.857
-----------------
-
1.002
126
Hexahydro-5-methylene-6a-methyl-1-(2H)-pentalenone, 139.
I r n m r (C6D6, 300 m h z )
127
Hexahy dro-5-methylene-6a-methyl-1-(2H)-pentalenone, 139.
13c NM R (C6D6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
□ cr
150.383
128.504
128.185
127.864
107.508
: esr' sxss s
OD -
128
2-methyl-5-J?-(2-methylethenyl)-1-((trimethylsilyl)oxy)-3-if-(2(trimethylsilylmethyl)prop-1-enyl)cyclohex-1-ene, 136.
1H N M R (C6D6, 300 MHz)
/"
4.001
o'
--------- 4 948
-------- 4 899
-------- 4 B H
----- - 4 . 7 7 0
:! I':
6.627
9.167
4 . 805
3 . 166
3.664
9.205
129
2-methyl-5-i?-(2-methylethenyl)-1-((trimethylsilyl)oxy)-3-J?-(2(trimethylsilylmethyl)prop-1-enyl)cyclohex-1-ene, 136.
13C N M R (C 6D 6, 75 MHz)
DEPT NM R (C6D6, 135° pulse)
149.391
146.769
144.215
114.606
109.834
109.435
42.161
37.590
36.298
32.389
31.652
31.182
26.390
23.318
21.105
____________ 1 5 . 4 5 1
------------------ 1 3 . 8 8 3
1.043
0.981
-
130
cz>Hexahydro-3a-methyl-2-methylene-6-J?-((2-methyl)prop-l-enyl)-4//-inden-4-one,
140.
1H NMR (C6D6, 300 MHz)
I
1.999
5.042
5 . 03?
5.030
4 *90
4.M 3
4.*11
4.*11
4.*72
4 M
4 7-ri
4.7 12
0.000
0.485
2.820
1.221
2.184
0.355
2.850
131
ciJ-Hexahydro-3a-methyl-2-methylene-6-i?-((2-methyl)prop-l-enyl)-4i/-inden-4-one,
140.
13c NMR (C6D6, 75 MHz)
DEPT NMR (C6D6, 135° pulse)
\
cr»
o
148.900
147.680
Xk
O
—
128.511
128.191
127.869
ro —
o
110.437
106.944
oO
OD
O
m
o
o
------------------
54.678
47.176
42.966
42.817
42.363
41.115
37.199
29.619
23.596
20.900
ro
o
o-
i
\
132
Trimethyl [(4-(2-(trimethylsilylmethyl)prop-1-enyl)-4H-1-benzopyran-2-yl)oxy] silane,
138.
I r NM R (C6D6, 300 MHz)
6 96'
6 96Z
P T - 6 9' :
»S6 9<\V” 6
w -6
V-6
V- 6
9<:
926
9:916
(Ti
O
cn
Ln
1 . 946
-------- 4 6 3 ;
_ ^
4 46:
4 44,
2fs:
2
0.956
3 -4f
3 13?
:: . 55C:!r
:4
1-359
i s::
: -st
3.366
5.166
3 .191
c 3:'
3.316
C. 3C6
3.296
c
9.414
9.903
:C . 2z45m
C23:
C .2 2:
133
Trimethyl[(4-(2-(trimethylsilylmethyl)prop-1-enyl)-4H-1-benzopyran-2-yl)oxy]silane,
138.
13c NMR (C6D6, 75 MHz)
DEPT NMR (C6D6, 135° pulse)
L
'
CD -
O
ao>—
152.270
144.774
o
K> •
O
128.949
128.512
128.191
127.870
125.512
123.825
116.735
1 1 0 . 46'
O
O76.217
CO
O
CTi
O
50.211
O
------------------------------------------------------------------
to
O
U
26.860
23.319
13.885
___________
O-
34.535
32.330
0.297
---------------------- 1 . 0 6 5
134
cw-2, 3, 3a, 9b-tetrahydro-2-methylene-cyclopenta[c][I]benzopyran-4//-(I)-one, 141.
lH NMR (CDCI3, 300 MHz)
1.000
1 :r
I 09"1
K^7O
94
7 055
SN- "1 .068
V- 7.039
W-' 036
L " 013
0.388
4
-3.44:_,
- 3 411--'
- 3.296
* 3 .1 8 1 .5
- 3 16S_
-
'Hr:
-3 .::5 0.207
- 3 ■:'<
-3 .2 6 -3.062
-3 : : : -
- 3. ■j Ci
0.216
SZ 2
0.208
I . SZC
- 2 -95
0.457
- 2 '9 0
772
-
-2.795
-2 7%
«
0.229
4 5 4 'I T
- 2 428-:-#
2.374
2 .36--
1;.579318
1
:3z
135
3, 3a, 9 b-tetrahydro-2 -methylene-cyclopenta[c][ I ]benzopyran-4//-(I )-one, 141.
13c NMR (CDCI3 , 75 MHz)
DEPT NMR (CDCI3 , 135° pulse)
cis-2,
170.249
151.275
146.793
128.899
128.620
124.928
123.960
117.425
77.860
77.436
77.012
_____ ______
------------------------
43.226
40.786
40.377
35.472
136
Diketone 165.
IR NMR (CDCI3 , 300 MHz)
O
(Ti
Ln
(Ti
O
Ln
Ln
Ln
O
r 2.859
r 2 . 95:
r 2.840
r 2.821
Ln
- 2 . 6:9
p 2 . 6 15
O
LU
Ln
1.000
r2 .::i
:t
p2.:53
r 2.233
p2.:30
r2.:C 4
LU
r2
O
2
J~ Ln
0
r 2 . 291
r 2 :
.-.
. *f -
P 2 • 33 1
r 2 225
r 2 . 0 12
H-*
"V
O
O
Ln
TI
Ti
3
- I 543
-1.825
326
-1.51*
- I ’ 54
-I
4?
66«
-16*:
662
137
Diketone 165.
13c NMR (CDCI3 , 75 MHz)
DEPT NMR (CDCI3 , 135° pulse)
211■614
210.575
200
:
180
160
140
120
-C
77
CD
447
77.023
76.599
50.189
------- ----- 4 8 . 8 9 7
_____ ______
_____ ______
----------- -------
42.248
41.707
30.036
29.014
27.981
26.420
25.354
24.900
138
Diketone 168.
IR NMR (CDCl3, 300 MHz)
O
UJ
un
UJ
o
NJ
Ln
V
K>
O
:
I
3.366^
V
O
LH
TJ
3
•
-1 .1 2 5
139
Diketone 168.
13c NMR (CDCI3 , 75 MHz)
DEPT NMR (CDCI3 , 135° pulse)
2 1 4 . 67C
211.96-)
200
180
1 60
140
120
100
80
77.959
77.534
■•7 . 1 0 6
60
40
• 46.48C
■4 4 .4 0 :
• 4 2 .2 7 5
■ 3 6. 99 1
• 34.41:
2S.3C1
26 . 85.
25.69'
20
0
ppm
\
140
Diketone 169.
IR NMR (CDCl3, 300 MHz)
<D-
—I —
CTt -
W —
------------ 2 . 7 3 7
1.000
N) -
------------ 1 . 1 4 9
5.576
O
-
ppm
141
Diketone 169.
13c NMR (CDCI3 , 75 MHz)
DEPT NMR (CDCI3 , 135° pulse)
77.833
77.410
76.987
______ —
-----------------------------
30.890
30.102
27.016
142
Diketone 171.
IR NMR (CDCl3, 300 MHz)
OJ
O
-J
O
N>
Ul
cn
o
Ul
Ui
ro
o
Ui
o
I<
I
o
OJ
Ui
rO
hD
3
UJ
O
IsO
^
in
5
O
3
"V
< ei
y6
V
O
Ui
T3
3
143
Diketone 171.
13c NMR (CDCI3 , 75 MHz)
DEPT NMR (CDCI3 , 135° pulse)
212.523
44 . 985
43.817
37.381
36.944
29.573
26.451
20.916